Novel 11-deoxy-11-substituted prostaglandins of the E and F series

ABSTRACT

This disclosure describes 11-deoxy-11-substituted members of the E 2 , F 2 , E 1 , F 1 , dihydro E 1  and dihydro F 1  prostaglandin series which are useful as hypotensive agents and as anti-ulcer agents.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 552,403, filed Feb. 24, 1975 U.S. Pat. No. 4,057,571, which is in turn a continuation-in-part of application Ser. No. 274,559, filed July 24, 1972 U.S. Pat. No. 4,141,914.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel organic compounds of the prostanoic acid class and their derivatives. In particular, the compounds of this invention are 11-deoxy-11-substituted derivatives of this class. The novel compounds of this invention embrace all of the optical antipodes, enantiomers, diastereoisomers, racemates, racemic mixtures and diastereoisomeric mixtures represented by the following general formulae; of which (A) represents the absolute configuration of the mammallian, naturally-occurring prostaglandins. ##STR1## wherein R is a member of the group consisting of alkyl groups of 3 to 7 carbon atoms, alkenyl groups of 3 to 7 carbon atoms, phenyl, and phenoxy-unsubstituted or substituted with one or two groups selected from the group consisting of lower alkyl, lower alkoxy, nitro, halogen and trifluoromethyl; R₁ is a member of the group consisting of lower alkyl, lower 1-alkenyl, phenyl, lower alkylthio, lower alkanoylthio, sulfhydryl, ω-di(lower alkyl)amino lower alkylthio, cyano, carboxamido, carboxylic acid and alkyl esters thereof, α-nitro lower alkyl, α,α-di(lower carboalkoxy) lower alkyl, α,α-dicarboxy lower alkyl, α-carboxy lower alkyl, di(lower alkyl)sulfonium halide, p-toluenesulfonylate or lower alkylsulfonate, formyl, lower alkanoyl, α,α-di(lower alkoxy)methyl, α,α-ethylenedioxy lower alkyl, α-hydroxy-lower alkyl radicals; R₂ is selected from the group consisting of hydrogen and an alkyl group having from 1 to 12 carbon atoms; R₃ and R₄ are members of the group consisting of hydrogen, fluorine and lower alkyl radicals, not necessarily the same for each use; X is a divalent moiety selected from the group consisting of ##STR2## wherein R₅ is selected from the group consisting of hydrogen, lower alkanoyl, lower alkylsulfonyl, tetrahydropyranyl and tri(lower alkyl)silyl; R₆ is selected from the group consisting of hydrogen and lower alkyl radicals with the proviso that when R₆ is lower alkyl, then R₅ is hydrogen; Y is a divalent radical selected from the group consisting of: ##STR3## the moiety of -C₅ -C₆ - is ethylene or cis-vinylene; the moiety -C₁₃ -C₁₄ - is ethylene or trans-vinylene; with the proviso that when -C₅ -C₆ - is cis-vinylene, then -C₁₃ -C₁₄ - must be trans-vinylene; with the third proviso that the bonds represented as embrace both possible configurations; and with the further proviso that the three substituents at C₈, C₁₂ and C₁₁ of the cyclopentenone ring are not each cis to each other at the same time.

Suitable lower alkyl and lower alkanoyl groups contemplated by the present invention are those having up to four carbon atoms such as, for example, methyl, ethyl, isopropyl, sec-butyl, formyl, acetyl, propionyl, iso-butryl, etc.

Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the novel compounds of the present invention when R₂ is hydrogen. The cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tri(lower alkyl)amine cations (e.g., triethylamine), procaine, and the like.

The novel compounds of the present invention are obtainable as yellow oils having characteristic absorption spectra. They are relatively insoluble in water but are relatively soluble in common organic solvents such as ethanol, ethyl acetate, dimethylformamide, and the like. The cationic salts of the compounds when R₂ is hydrogen are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively soluble in water, methanol, and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.

The C₁₁ substituents of the compounds of this invention can be introduced by a conjugate addition reaction with Δ¹⁰ -9-keto prostenoic acid and their derivatives, commonly referred to as prostaglandins of the A series, or by a subsequent transformation of an already present C₁₁ -substituent.

A substituent at C₁₁ trans to the C₁₂ chain is said to be in the α configuration and its bond to C₁₁ is represented by . Conversely, a constituent at C₁₁ cis to the C₁₂ chain is in the β configuration (also termed 11-epi)and its bond to C₁₁ is represented by a solid line; a bond represented by a indicates that both the 11α and 11β possibilities are embraced. When the oxy substituent at C₁₅ is in the α or "normal" configuration, the bond is represented by and when it is in the β or "epi" configuration the bond is indicated by .

Among the reagents which can be utilized for conjugate addition are lithio di(lower alkyl)cuprates (e.g. lithio dimethylcuprate), lithio di(lower 1-alkenyl)cuprates, lithio diphenyl cuprate, lower alkyl mercaptans, ω-di(lower alkyl)amino lower alkyl mercaptans, thio lower alkanoic acids, acetone cyanohydrin (for cyanide introduction), 1-nitro-lower alkanes, di(lower alkyl)malonates as well as di(lower alkyl)mono-lower alkyl substituted malonates, lower primary and secondary alcohols, 1,3-dioxolan and lower 2-alkyl 1,3-dioxolans. With the exception of the lithio di(lower alkyl)cuprates and lithio di(lower alkenyl)cuprates, the various reagents generally require catalytic conditions for effective conjugate addition. The appropriate conditions for each reagent are apparent from the examples included herein. Illustrative conjugate addition reacts using the naturally occurring l-15-O-acetylprostaglandin-A₂ methyl ester (I) are shown in Flowsheets A through G, wherein R₇ is a lower alkyl group, lower 1-alkenyl group, or phenyl, R₈ is a lower alkanoyl group, R₉ is hydrogen or a lower alkyl group, R₁₀ is a lower alkyl group, and X is halogen, p-toluenesulfonyloxy, or lower alkylsulfonyloxy. ##STR4##

In accordance with Flowsheet A, treatment of 15-O-acetylprostaglandin-A₂ methyl ester with a lithio-dialkyl, dialkenyl or diphenylcuprate provides a mixture of the 11-deoxy-11-substituted-15-O-acetylprostaglandin-E₂ methyl ester and the 11-deoxy-11-substituted-15-substituted-prostaglandin-E₂ methyl ester. The use of the 15-hydroxy function to prevent the interaction of the 15-acetoxy group is described hereinbelow. Also in accordance with Flowsheet A is shown the conjugate addition of α,α-dicarboxylower alkyl and α-nitro lower alkyl groups.

The preparation of 11-deoxy-11-lower alkanoylthio-15-O-acetylprostaglandin-E₂ methyl esters by the heating of I in a thiolcarboxylic acid is illustrated in Flowsheet C. Also illustrated is the preparation of the 11-deoxy-11α-lower alkylthio-15-O-acetylprostaglandin-E₂ methyl ester (X) and its subsequent methanolysis to give XI.

The utility of XI to prepare PGA₂ methyl ester (XIII) is shown in Flowsheet D; (XIII) is not directly obtainable from I by the usual chemical procedures.

The preparation of the free 15-hydroxy derivative (XIII) from (I) is difficult to achieve directly by the usual acid-or-base-catalyzed conditions of hydrolysis. Under these circumstances (I) is too unstable and elimination to the novel tetraene (XIII) is observed. ##STR5##

In order to prepare the free 15-hydroxy derivative we have developed a convenient and novel procedure, which we consider to be a part of this invention. This procedure involves the conjugate addition to the diester of an alkyl/mercaptan (e.g., methyl mercaptan or ethyl mercaptan) to give the 11-alkylthio derivative (X). Saponification of diester (X) with potassium carbonate in the presence of excess alkyl mercaptan then procedes smoothly to provide the free 15-ol 11-alkylthio derivative (XI). The presence of alkyl mercaptan during this treatment presumably maintains the 11-alkylthio group, which otherwise would be eliminated under these conditions to give the Δ¹⁰ -9-keto system, unstable to saponification conditions. Thus, in effect this procedure protects this latter system during saponification. The Δ¹⁰ -function can then be regenerated under conditions to which it is stable by enhancing the leaving potential of the alkylthio group by conversion to a sulfonium salt (XII) which is eliminated readily with sodium bicarbonate to give the methyl ester (XIII) of PGA₂. The overall yield for the conversion of (I) to (XIII) is quite high, on the order of 70-85%, and several of the steps can be combined.

The free 15-ol (XIII) is a useful intermediate. For example, treatment with lithium dialkyl cuprates provides high yields of the 11-lower alkyl derivatives without involvement of the 15-oxy function. When the same reagent is used to treat the diester (I) the 15-acetoxy function becomes involved and a substantial portion of the product is the 11,15-di(lower alkyl) derivative (III).

As illustrated in Flowsheet E, the treatment of the diester (I) with acetone cyanohydrin affords a mixture of 11α and 11β nitriles. Hydrolysis using saturated aqueous potassium cyanide in methanol yields the two epimeric nitriles (XV) and (XVI), separable by column chromatography (Example 212).

A unique photensitized addition of lower primary and secondary alcohols, 1,3-dioxolan, and 2-substituted 1,3-dioxolans to the enone system of prostaglandins-A is also disclosed in this invention and is illustrated in Flowsheet G.

The irradiation of a solution of 15-O-acetylprostaglandin-A₂ methyl ester (I) in an alcohol containing benzophenone using a pyrex filter and medium pressure lamp provides the 11-deoxy-11-substituted-15-O-acetylprostaglandin-E₂ methyl ester (XXI). Likewise irradiation using 1,3-dioxolans as solvent yields 11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methyl ester derivatives (XX); acid hydrolysis of which provides the corresponding 11-formyl or acyl derivatives.

Other novel compounds embraced by this invention can be prepared by further transformations of the above-described conjugate addition products. Thus, for example, hydrolysis of the malonate addition product (VI) furnishes the 11-(α,α-dicarboxy lower alkyl) derivative (VII), decarboxylation of which provides the 11-(α-carboxy lower alkyl) derivative (VIII). Treatment of the 11-cyano derivative (XIV), with alkaline hydrogen peroxide gives the 11-carboxamido diester (XVII), which on mild hydrolysis (three equivalents of potassium hydroxide, three hours, ambient temperature) gives the corresponding 15-hydroxy carboxylic acid (XVIII). Vigorous alkaline hydrolysis of (XVIII) then yields the 11-carboxylic acid derivatives (XIX).

Certain of the other products embraced by this invention can be obtained by substituting members from the following Table of prostaglandins A for l-15-O-acetylprostaglandin-A₂ methyl ester (I) or the corresponding free 15-ol (XIII) of Flowsheets A through G:

TABLE I

l-13-dihydroprostaglandin-A₁ ^(a)

l-prostaglandin-A₁ ^(a)

l-prostaglandin-A₂ ^(b)

l-15-epi-O-acetylprostaglandin-A₂ methyl ester^(c)

l-15-epi-prostaglandin-A₂ ^(c)

dl-prostaglandin-A₁ ^(d)

l-15-methylprostaglandin-A₁ methyl ester^(e)

d-15-methylprostaglandin-A₂ methyl ester^(e)

l-16,16-dimethylprostaglandin-A₁ ^(f)

l-16(S)-methylprostagladin-A₂ ^(g)

l-16(R)-methylprostaglandin-A₂ ^(g)

l-16(S)-methylprostaglandin-A₁ ^(g)

l-16(R)-methylprostaglandin-A₁ ^(g)

l-16,16-difluoroprostaglandin-A₂ ^(h)

l-16-fluoroprostaglandin-A₂ ^(h)

l-20-methylprostaglandin-A₂ (Example 108)

l-20-ethylprostaglandin-A₂ (Example 103)

d,l-17,20-tetranor-16-p-fluorophenoxyprostaglandin-A₂ (Example 113)

l-17,20-tetranor-16-p-fluorophenoxyprostaglandin-A₂ (Example 106)

d,l-17,20-tetranor-16-m-chlorophenoxyprostaglandin-A₂ (Example 111)

l-17,20-tetranor-16-m-chlorophenoxyprostaglandin-A₂ (Example 104)

d,l-17,20-tetranor-16-m-trifluoromethylphenoxyprostaglandin-A₂ (Example 114)

l-17,20-tetranor-16-m-trifluoromethylphenoxyprostaglandin-A₂ (Example 107)

l-17,20-tetranor-16-phenoxyprostaglandin-A₂ (Example 105)

d,l-17,20-tetranor-16-phenoxyprostaglandin-A₂ (Example 112)

REFERENCES

The configuration of the various substituents introduced at C-11 has been established for nearly all of the compounds disclosed herein.

In the case of the 11-alkylthio derivatives, a single isomer (11α) almost totally predominates although traces of the 11β epimer are detected. In the 11-alkyl and 11-alkenyl series the available evidence indicates that a single isomer predominates. The evidence and theoretical considerations leads to the assignment to these epimers of the 11-normal configuration, i.e., a trans-relationship between the 11-substituent and the adjacent side chain.

The introduction of the 11-cyano moiety appears to yield mearly equal amounts of both the 11α and 11β epimers. This epimeric mixture is obtained when one uses either a diester such as l-15-O-acetylprostaglandin-A₂ methyl ester or a free hydroxy acid such as l-PGA₂. These epimers are separable from each other by chromatographic procedures.

The stereochemistry of the 11-hydroxy-lower alkyl derivatives is dependent upon the alcoholic reagent utilized. Methanol leads to a separable epimeric mixture of 11α-hydroxymethyl and 11β-hydroxymethyl epimers in about a 1:3 ratio, respectively. With isopropanol the product is largely the 11α-(1-hydroxy-1-methylethyl) derivative.

The photeosensitized introduction of 1,3-dioxolan yields a separable mixture of 11α and 11β-(1,3-dioxolan-2-yl) derivatives in a 1:3 ratio.

The 11α-substituted products of this invention can be epimerized to a mixture containing the 8-normal and 8-iso epimers. This is illustrated in Flowsheet H using 11-deoxy-11α-hydroxymethylprostaglandin-E₂ as an example. ##STR6##

Esterification of the free 15-hydroxy function as well as of the free carboxylic acid function by the usual procedures provides the other ester derivatives of this invention.

The products of this invention that have the 15-oxy function in the (S) or "normal" configuration can be converted to the alternate (R) or "epi" configuration by two procedures, illustrated below in Flowsheet I for the 11-methyl series.

Treatment of (XXV) with a solution of sodium formate in formic acid induces racemization of the 15-oxy function and a mixture of the 15(R) and 15(S) formyloxy derivatives (XXIII) and (XXIV) are obtained. Separation of this mixture by chromatography provides the individual components and formate hydrolysis gives the original 15(S)-ol and (XXV) and the inverted 15(R)-ol (XXVIII).

Epimerization of the 15(S)-ol (XXV) can be accomplished by conversion to a sulfonyloxy derivative (XXVI), such as methanesulfonyloxy, by treatment with methanesulfonic acid anhydride at low temperatures in the presence of an organic base such as triethylamine. The sulfonyloxy derivative (XXVI) is then treated with tetraethyl ammonium formate in a suitable organic solvent to produce the inverted 15(R)-formyloxy derivative (XXIV). Formate hydrolysis then provides the 15(R)-alcohol (XXVIII).

Likewise, compounds of this invention that contain the 15(R)-hydroxy function can be epimerized to either the 15(S) or a mixture of 15(S) and 15(R) derivatives. ##STR7##

The 9-oxo derivatives (E-series) of this invention can be converted to the corresponding 9-hydroxy derivatives (F-series) by either a non-selective carbonyl reduction with a reagent such as sodium borohydride in an alcohol solvent, or stereoselectively with a reagent such as lithium-9b-boraphenalyl hydride (XXIX) [H. C. Brown and W. C. Dickason, Journ. Amer. Chem. Soc. 92, 709 (1970)] or lithium tri-sec-butylborohydride (XXX) in an ether solvent [H. C. Brown and S. Krishnamurthy, Journ. Amer. Chem. Soc., 94, 7159 (1972)]. ##STR8## In accordance with Flowsheet J, treatment of the 9-keto derivative (XXXI) in a solvent such as ethanol with sodium borohydride will provide a mixture of the corresponding 9α and 9β hydroxy products which can be separated into their individual components by the usual chromatographic techniques. Stereoselectivity in this reduction can be realized by using a bulky reagent such as (XXIX) or (XXX) in a solvent such as tetrahydrofuran to provide, after borane hydrolysis, predominately, the cis-hydroxy (9α) species (XXXII) when the 11-substituent is in the α-configuration. In the particular case of compounds containing the 8-iso configuration (the two side chains being cis to each other) sodium borohydride again yields a mixture of 9α and 9β hydroxy compounds. However, the use of the bulky stereoselective reagents (XXIX) and (XXX) will yield predominantly the 9β hydroxyl, that is, the hydroxyl at the 9 position is cis to the carboxylic acid side chain. These reductions are illustrated in Flowsheet K. ##STR9##

The novel compounds of this invention which are members of the prostaglandin E₂ and F₂ series can be converted to other novel derivatives of the 11-deoxy prostaglandin E₁ and F₁ series by preferential reduction of the Δ⁵ cis-double bond. This can be achieved by careful catalytic hydrogenation in the presence of a metal catalyst such as palladium-carbon or RhCl [P(C₆ H₅)₃ ]₃ or by use of diimide. Selectivity for the reduction of the Δ⁵ bond can be enhanced by first converting the 15-ol to a derivative which sterically hinders the approach to the competing Δ¹³ double bond. Useful 15-hydroxy derivatives for this purpose include the tetrahydropyranyl derivative and the dimethylisopropylsilyl ether.

This invention also includes the novel 11-substituted derivatives of 13-dihydro-11-deoxy-prostaglandin E₁ and F₁. These compounds, in which all of the double bonds are saturated, can be prepared by catalytic hydrogenation in the usual manner of the corresponding members of the E₃, F₃, E₂, F₂, E₁, or F₁ series. (F derivative of the 1 or dihydro-1 series can be prepared from the corresponding F₂ derivatives by partial or full hydrogenation as just described or by reduction of the 9-carbonyl function of the corresponding E compound).

The compounds of this invention are useful as protective agents against the ulcerogenic and gastrointestinal effects induced by certain otherwise valuable pharmaceutical agents, particularly non-steroidal anti-inflammatory agents such as indomethacin, phenylbutazone, and aspirin. Indicative of the serious nature of this problem are the following statements concerning indomethacin (Indocin®) taken from Physician's Desk Reference 1972 (Medical Economics Inc., Oradell, N.J.), p. 964.

"Gastrointestinal Effects:

Because of the occurrence and, at times, severity of gastrointestinal reactions to INDOCIN, the prescribing physician must be continuously alert for any sign of symptom signalling a possible gastrointestinal reaction. The risks of continuing INDOCIN therapy in the face of such symptoms must be weighed against the possible benefits to the individual patient. The gastrointestinal effects may be reduced by giving the drug immediately after meals, with food, or with antacids. As advancing years appear to increase the possibility of adverse reactions, INDOCIN should be used with concomitantly greater care in the aging."

"Gastroinestinal Reactions:

Single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small intestines. Fatalities have been reported to occur in some instances. Gastrointestinal bleeding without obvious ulcer formation. Perforation of pre-existing sigmold lesions (diverticulm, carcinoma, etc.). Increased abdominal pain in ulcerative colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur rarely. Gastritis may persist after the cessation of the drug. Nausea, vomiting, anorexia, epigastric distress, abdominal pain and diarrhea."

It is further to be noted that although prostaglandins in general are not effective when administered by oral route, the compounds of this invention are effective orally. The assay to determine the protective effect of these compounds is carried out in the following manner.

Rats were starved for 48 hours (water was given ad libitum). Indomethacin (20 mg./kg. of body weight) was administered by the subcutaneous route and one-half the dose of the test compound was administered by gavage at the same time. After three hours, the second half of the test compound was administered, also by gavage. Five hours after the administration of indomethacin the animals were decapitated and the stomachs removed. The stomachs were washed with distilled water, blotted on gauze, cut along the larger curvature, and the contents rinsed with distilled water. The stomachs were spread out, pinned on a cork and visualized under magnifying glass for ulcers. The criteria for scoring of ulcers was as previously reported. [Abdel-Galil et al. Brit. J. Pharmac. Chemotherapy 33:1-14 (1968)].

Score

0--Normal Stomach

1--Petechial hemorrhage of pin point ulcers

2--1 or 2 small ulcers

3--Many ulcers, a few large

4--Many ulcers, mainly large

Control animals treated with indomethacin but not test compound consistenly give scores of about 2.5-3.5. Control animals treated with neither indomethacin not test compound give scores of about 0.5-0.8. The results obtained in this assay with typical compounds of the present invention are set forth in the table below. Compounds diminishing the control ulcer score by 0.5 unit or more are considered to be active.

                                      TABLE I                                      __________________________________________________________________________                        Total oral                                                                             SCORE                                                                  dose; mg./kg.                                                                          Treated                                             Compound           of body weight                                                                         Animals                                                                             Controls                                       __________________________________________________________________________     l-11α/β-cyano-11-deoxyprostaglandin-                                E.sub.2 -methyl ester                                                                             25      1.3  2.7                                            l-11α/β-cyano-11-deoxyprostaglandin-                                E.sub.2            12.5    1.2  2.5                                            l-11α-nitromethyl-11-deoxyprosta-                                        glandin-E.sub.2    100     1.0  3.2                                            l-11α-methylthio-11-deoxyprosta-                                         glandin-E.sub.2 15-o-acetate methyl                                            ester              50      2.0  2.7                                            l-11α-methyl-11-deoxyprostaglandin-                                                         6.25    2.5  3.0                                            E.sub.2            12.5    2.0  3.0                                                               25.0    1.7  3.0                                            l 11α-carboxamido-11-deoxyprosta-                                        glandin-F.sub.2 α                                                                           50      2.3  3.2                                            l-11α/β-cyano-11-deoxyprostaglandin-                                                   50      1.3  3.0                                            E.sub.2 15-o-acetate methyl ester                                                                 12.5    2.0  2.7                                            l-11α-methyl-11-deoxy-13-dihydro-                                                           50      1.7  3.0                                            prostaglandin-E.sub.1                                                                             12.5    2.3  3.0                                            l-11α-methyl-11-deoxyprostaglandin-                                      F.sub.2 α    25      1.8  2.7                                            l-11α,15-dimethyl-11,15-bisdeoxy-                                        prostaglandin-E.sub.2 α                                                                     50      2.2  3.0                                            l-11α-cyano-11-deoxyprostaglandin-                                       F.sub.2 α    25      1.3  2.8                                            l-11α-ethyl-11-deoxyprostaglandin-                                       E.sub.2            25      2.2  3.0                                            l-11α-ethyl-11-deoxyprostaglandin-                                       F.sub.2 α    25      2.2  3.0                                            l-11α-phenyl-11-deoxyprostaglandin-                                      F.sub.2 α    25      2.0  3.9                                            l-11α-nitromethyl-11-deoxyprosta-                                        glandin-F.sub.2 α                                                                           50      1.8  2.5                                            l-11α-methylthio-11-deoxyprosta-                                         glandin-F.sub.2 α                                                                           12.5    1.2  2.7                                            __________________________________________________________________________

The novel compounds of the present invention are effective inhibitors of gastric acid secretion and of ulcer development in experimental animals, and thus are potentially valuable as agents for the control of gastric secretion and of gastric erosion and as anti-ulcer agents. Gastric acid secretion inhibitory action is usually measured by the "Shay rat" procedure.sup.(1,2) with some modifications as follows.

The rats (male, CFE strain) were starved for 48 hours (water was given ad libitum) to permit evacuation of stomach contents. On the morning of the experiment, under ether anesthesia, the abdominal region was shaved and a midline incision (1-11/2") was made with a scapel. With the help of a closed curved hemostat the duodenum was picked up. Upon getting the duodenum into view, fingers were used to pull the stomach through the opening, the stomach was then gently manipulated with fingers to rid stomach of air and residual matter which were pushed through the pylorus. Two-5 inch sutures were drawn under the pyloric-duodenal puncture. A ligature, at the juncture, was formed with one of the threads. The second ligature was also formed but not tightened.

The test compound or the vehicle, usually 1 ml./100 g. body weight, were injected into the duodenum as close as possible to the first ligature. After injection the second ligature was tightened below the injection site to minimize leakage. The stomach was placed back through the opening into the abdominal cavity, the area of incision was washed with saline and the incision was closed with autoclips. (Occasionally, instead of an intraduodenal injection, animals were dosed by the oral or subcutaneous route. In the latter case, dosing was done thirty to sixty minutes before the operation.)

Three hours later, the rats were decapitated and exanguinated, taking care that blood did not drain into the esophagus. The abdominal cavity was exposed by cutting with scissors and the esophagus close to the stomach was clamped off with a hemostat, the stomach was removed by cutting above the hemostat (the esophagus was cut) and between the two sutures. Extraneous tissue was removed, the stomach washed with saline and blotted on gauze. A slit was carefully made in the stomach which was held over a funnel and the contents were collected in a centrifuge tube. The stomach was further cut along the outside edge and turned inside out. Two ml. H₂ O were used to wash the stomach contents into the respective centrifuge tube. The combined stomach contents and wash were then centrifuged out for 10 minutes in the International Size 2 Centrifuge (setting at 30). The supernatant was collected, volume measured and recorded, 2 drops of a phenylphthalein indicator (1% in 95% ethanol) were added and the solution was titrated with 0.02 N NaOH (or with 0.04 N NaOH when large volumes of stomach contents were encountered) to pH 8.4 (because of usual coloring of the stomach contents, phenolphthalein was only used to permit visual indication that the end point was near) and the amount of acid present was calculated.

Compounds inducing inhibition of gastric acid secretion of 20% or more were considered active. In a representative operation, and merely by way of illustration, the results obtained with this assay with typical compounds of the present invention are given in Table II below.

                  TABLE II                                                         ______________________________________                                                         Intraduodenal                                                                  dose, mg./kg. Percent                                          Compound        of body weight                                                                               Inhibition                                       ______________________________________                                         l-11α/β-cyano-11-deoxy-                                             prostaglandin-E.sub.2 15-                                                      o-acetyl methyl                                                                ester           25            51                                               l-11α/β-cyano-11-deoxy-                                             prostaglandin-E.sub.2                                                          methyl ester    50            33                                               l-11α/β-cyano-11-deoxy-                                                             50            79                                               prostaglandin-E.sub.2                                                                          25            31                                               l-11α-cyano-11-deoxy-                                                    prostaglandin-F.sub.2 α                                                                  50            43                                               l-11α-ethylthio-11-                                                      deoxyprostaglandin-                                                            E.sub.2 15-o-acetyl                                                            methyl ester    50            27                                               l-11α-methylthio-11-                                                     deoxyprostaglandin-                                                            E.sub.2 15-o-acetyl                                                            methyl ester    50            35                                               l-11α-methyl-11-deoxy-                                                   prostaglandin-E.sub.2                                                                          50            63                                               l-11α-methyl-11-deoxy-                                                   prostaglandin-F.sub.2 α                                                                  50            70                                               l-11α-methyl-11-deoxy-                                                   13-dihydroprosta-                                                              glandin-E.sub.1 50            45                                               1-11α-methyl-11-deoxy-                                                   prostaglandin-E.sub.2                                                          15-o-acetyl methyl                                                             ester           50            63                                               l-11α,15-dimethyl-11,                                                    15-bisdeoxyprosta-                                                             glandin-E.sub.2 methyl                                                         ester           50            40                                               l-11α,15-dimethyl-11,                                                    15-bisdeoxyprosta-                                                             glandin-E.sub.2 50            60                                               l-11-carboxamido-11-                                                           deoxyprostaglandin-                                                            E.sub.2         50            27                                               l-11-carboxamido-11-                                                           deoxyprostaglandin-                                                            F.sub.2 α 50            27                                               l-11α-nitromethyl-11-                                                    deoxyprostaglandin-                                                            E.sub.2         100           74                                               l-11α-vinyl-11-deoxy-                                                    prostaglandin-E.sub.2                                                                          50            59                                               l-11α-methylthio-11-                                                     deoxyprostaglandin-                                                            E.sub.2 methyl ester                                                                           100           55                                               l-11α-isopropyl-11-                                                      deoxyprostaglandin-                                                            E.sub.2         50            42                                               l-11α-phenyl-11-deo-                                                     deoxyprostaglandin-                                                            E.sub.2         50            58                                               l-11α-(1-hydroxy-1-                                                      methylethyl)-11-                                                               deoxyprostaglandin-E.sub.2                                                                       8*          31                                               l-11β-hydroxymethyl-                                                      11-deoxyprosta-                                                                glandin-E.sub.2   8*          44                                               l-11α-nitromethyl-11-                                                    deoxyprostaglandin-                                                            F.sub.2 α 50            38                                               l-11α-methylthio-11-                                                     deoxyprostaglandin-                                                            F.sub.2 α 50            61                                               ______________________________________                                          *subcutaneous route of administration                                    

Inhibition of basal gastric acid secretion can be determined by the following procedure.

Female Sprague-Dawley rats weighing 140-160 grams are fasted in individual cages for 18-24 hours. The rats are then lightly anesthetized with ether and their front teeth extracted to avoid destruction of the plastic cannula. A midline incision is then made and the stomach and duodenum exposed. A flanged polyvinyl tube is inserted into the fundic portion of the stomach and secured with a purse string suture line using 4-O Mersilene. The rat is then dosed by injection of the compound into the duodenum (1.0 ml. per 100 gram body weight). After dosing, the abdominal wall and skin are closed using metal wound clips. The rate is replaced in a cage containing a longitudinal slit to allow the polyvinyl tube to hang freely. An 8 ml. plastic collecting tube is attached to the flanged cannula and hangs freely below the cage. The first 30 minute sample is discarded designating this time as zero. The collecting tube is attached again and samples removed at the end of 60 and 120 minutes. These samples are referred to as "A" and "B" in the table. The hourly samples are then transferred to a 15 ml. centrifuge and centrifuged for 5-10 minutes. Total and sediment volume are then recorded with the supernatent volume being used as volume of secretion. A 1 ml. or less aliquot is then removed and placed in a 50 ml. beaker containing 10 ml. of distilled water. This sample is then titrated using 0.01 N NaPH to pH 7.0 using a Beckman zeromatic pH meter. Volume, titratable acidity (mew/L) and total acid output (ueq/hour) are recorded. Percent inhibition is determined by comparison with the appropriate control. Groups of three rats were used for preliminary testing, and groups of six rats were used for dose-response evaluations. All compounds are administered in a vehicle consisting of 0.5% methocel, 0.4% tween 80, and saline at a constant volume of 1 ml./100 gram rat. Samples are dispersed by sonification. Percent inhibition is calculated on basis of concurrent vehicle control.

In Table III which follows is given the effect on total acid output after 60 minutes and 120 minutes of intraduodenal dose, of representative compounds of this invention.

                                      TABLE III                                    __________________________________________________________________________     Inhibition of Total Acid Output in the Acute Gastric Fistula Rat                                           % Inhibition of Total                                                          Acid Output                                                            Dose mg./kg.                                                                           After 60                                                                             After 120                                    Compound            of body weight                                                                         minutes (A)                                                                          minutes (B)                                  __________________________________________________________________________     l-11-acetylthio-11-deoxyprostaglandin-E.sub.2                                                      10      66    68                                           l-11α-ethylthio-15-o-acetyl-11-deoxy-                                                        10      80    24                                           prostaglandin-E.sub.2 methyl ester                                                                 5       19    59                                                               2.5     54    51                                           l-11α-ethyl-11-deoxyprostaglandin-E.sub.2                                                    10      57    66                                           l-11β-cyano-11-deoxyprostaglandin-E.sub.2                                                     10      26    43                                           l-11α-cyano-11-deoxyprostaglandin-E.sub.2                                                    10      49    18                                           l-11-cyano-15-o-acetyl-11-deoxy-                                               prostaglandin-E.sub.2 methyl ester                                                                 10      40    34                                           l-11-carboxamido-11-deoxyprostaglandin-                                        E.sub.2             10      27    35                                           l-11-mercapto-11-deoxyprostaglandin-F.sub.2 α                                                10      44    55                                           l-11β-hydroxymethyl-11-deoxyprosta-                                       glandin-F.sub.2 α                                                                            10      0     43                                           l-11α-(1-hydroxy-1-methylethyl)-11-deoxy-                                prostaglandin-F.sub.2 α                                                                      10      36    35                                           l-11α-vinyl-11-deoxyprostaglandin-F.sub.2 α                                            5       53    67                                                               2.5     15    37                                           l-11α-isopropyl-11-deoxyprostaglandin-                                   F.sub.2 α     10      44    35                                           l-9α-hydroxy-11α,15-dimethyl-5-cis,                                13-trans-prostadienoic acid                                                                        10      25    20                                           l-11α-hydroxymethyl-11-deoxyprosta-                                      glandin-F.sub.2 β                                                                             5       49    49                                           l-11α-hydroxymethyl-15-o-acetyl-11-                                      hydroxyprostaglandin-F.sub.2 β methyl ester                                                   5       47    33                                           __________________________________________________________________________

An important consideration in the use of prostaglandin like substances for the inhibition of gastric acid secretion and the treatment of ulcers, etc. is that they do not at the same time induce diarrhea, a common phenomenon observed on administration of the prostaglandins. It is therefore unexpected and novel that in general, the compounds of this invention are not diarrheagenic at dose levels at which they are effective gastric acid secretion inhibitors. One measure of diarrheagenic potential is the ileal ligated rat assay, a description of which follows directly.

Female Sprague-Dawley rats (Charles River Laboratories) weighing less than 100 grams are fasted in individual cages for at least 18 hours. They are then anesthetized with ether and a midline incision made. The duodenum is exposed and the test drug or control injected intraduodenally. The ileocecal junction is then exposed and the terminal ileum is ligated using 3-0 silk thread just proximal to the junction. The incision is then closed using wound clips. Rats are placed back in individual cages without food or water for four hours. After this time the rats were sacrificed, the stomach and small intestine carefully removed, and cleaned of adherent mesentery. The removed portion of gut is then weighed to the nearest 0.1 gram. Compounds inducing diarrhea such as prostaglandins, cholera toxin, etc. produce an increase in weight of the ligated intestine. This increase from control is noted in Table IV, as change in weight in grams after standardizing weights of gut to grams/100 gram rat. An increase in intestinal weight of about 1.0 g. is considered indicative of diarrheagenic potential.

When measured by this assay at effective gastric acid secretion inhibiting doses, as determined by the acute rat fistula assay representative novel compounds of Table IV are non-diarrheagenic.

                  TABLE IV                                                         ______________________________________                                         Ideal-Ligated Rat Assay                                                                                      Increase                                                         Intraduodenal In weight                                                        dose, mg./kg. of intes-                                        Compound        of body weight                                                                               tine, g.                                         ______________________________________                                         l-11-acetylthio-11-                                                                            20            -0.1                                             deoxyprostaglandin-E.sub.2                                                                     10            -0.02                                            l-11α-ethylthio-11-                                                      deoxyprostaglandin-E.sub.2                                                                     10            -0.2                                             l-11α-vinyl-11-deoxy-                                                    prostaglandin-F.sub.2 α                                                                  10            -0.36                                            l-11α-hydroxymethyl-                                                     11-deoxyprostaglandin-                                                         F.sub.2 β  10            +0.6                                             l-11α-hydroxymethyl-                                                     15-O-acetyl-11-deoxy-                                                          prostaglandin-F.sub.2 β                                                   methyl ester    10            + 0.15                                           ______________________________________                                    

The E-type prostaglandin of this invention show bronchodilator activity in experimental animals and are potentially useful in the treatment of bronchial asthma.

Bronchodilator activity was determined in guinea pigs against bronchospasms elicited by intravenous injections of 5-hydroxytryptamine, histamine or acetylchlorine by the Konzett procedure. [See J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995 (1968).]

In the Table which follows bronchodilator activity for representative compounds of this invention against one or more of the three spasmogenic agents is expressed as an ED₅₀ determined from the results obtained with three logarithmic cumulative intravenous doses.

                                      TABLE V                                      __________________________________________________________________________     Bronchodilator Activity (Konzett Assays)                                       ED.sub.50, mg./kg.                                                                                 Spasmogenic Agent                                                              5-hydroxy-     acetyl-                                     Compound            tryptamine                                                                            histamine                                                                              choline                                     __________________________________________________________________________     l-11α-methyl-11-deoxy-13-dihydro-                                        prostaglandin-E.sub.1              0.773                                       l-11α-cyano-11-deoxyprostaglandin-F.sub.2 α                                                   1.66                                                l-11α-methyl-11-deoxyprostaglandin-F.sub.2 α                                           0.038  0.013                                               l-11α-methyl-11-deoxyprostaglandin-E.sub.2                                                   0.0022 0.050   1.19                                        l-11α,15-dimethyl-11,15-bis-deoxy-                                       prostaglandin-E.sub.2                                                                              18.1                                                       l-11α/β-cyano-11-deoxy-prostaglandin-E.sub.2                                            .0036  0.0054  0.091                                       l-11α-vinyl-11-deoxyprostaglandin-E.sub.2                                                    1.20   1.30                                                l-11α-isopropyl-11-deoxyprosta-                                          glandin-E.sub.2     8.95                                                       l-11α-phenyl-11-deoxyprostaglandin-E.sub.2                                                   .46                                                        l-11α-carboxamido-11-deoxprosta-                                         glandin-E.sub.2     1.7    0.53                                                l-11α-carboxymethyl-11-deoxyprosta-                                      glandin-E.sub.2     5.5    3.4     4.6                                         l-11α-dicarboxymethyl-11-deoxy-                                          prostaglandin-E.sub.2                                                                              3.3                                                        l-11α-nitromethyl-11-deoxyprosta-                                        glandin-E.sub.2            1.4     1.7                                         l-11α-cyano-11-deoxyprostaglandin-F.sub.2 α                                            0.03   0.019   0.051                                       l-11α-methylthio-11-deoxyprosta-                                         glandin-F.sub.2 α                                                                            2.63   1.6                                                 l-11α-ethyl-11-deoxyprostaglandin-E.sub.2                                                           1.24    3.9                                         l-11β-hydroxymethyl-11-deoxyprosta-                                       glandin-E.sub.2     0.30   0.065   0.25                                        l-11β-cyano-11-deoxyprostaglandin-E.sub.2                                                     3.1    54.9                                                l-11α-cyano-11-deoxyprostaglandin-E.sub.2                                                    0.30 × 10.sup.-3                                                                1.4 × 10.sup.-3                                                                  5.3 × 10.sup.-3                       __________________________________________________________________________

The novel compounds of the present invention also have potential utility as hypotensive agents, abortifacients, agents for the induction of labor, agents for the induction of menses, fertility-controlling agents, central nervous system regulatory agents, salts and water-retention regulatory agents, diuretics, and as inhibitors of platelet aggregation. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of other of the novel compounds of this invention.

This invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 Isolation of the methyl ester of 15-O-acetylprostaglandin A₂ from Plexaura Homomalla (esper)

Specimens of Plexaura Homomalla (esper) are collected in Puerto Rican waters, air dried and stored under a nitrogen atmosphere at 0° C. The cortex is removed, ground and extracted with isomeric hexanes. The organic solvent is evaporated in vacuo to afford a prostaglandin containing residue. The residue is dissolved in nitromethane and extracted with isomeric hexanes. The nitromethane solution is evaporated to give a residue that is approximately 50% by weight of the residue prior to the nitromethane treatment. This process, in addition to the removal of unwanted materials, (largely fatty esters), also has the benefit of selectively removing the sterols that have nearly the same rf index on silica gel as that of the methyl ester of 15-O-acetylprostaglandin A₂.

Purification of the residue via dry column chromatography using acid washed silica gel and 5% ethyl acetate as elutant yields the 15-O-acetyl-prostaglandin A₂ methyl ester and prostaglandin A₂ methyl ester. The combined yield of the two prostaglandins is 1-2%.

The configuration of the C-15 carbon is established by degradation with ozone followed by chromic acid oxidation to yield α-acetoxyheptanoic acid. The configuration of the acetoxy grouping is established by comparison of the circular dichromism curves of α-acetoxyheptanoic acid and D-α-acetoxypropanoic acid prepared from the calcium salt of D-lactic acid (R-configuration). Compounds of like configuration will display curves of the same sign. D-α-acetoxypropanoic acid displays a negative circular dichromism curve whereas the degradation product, α-acetoxyheptanoic acid gives a positive circular dichromism curve.

EXAMPLE 2 Preparation of 11-deoxy-11α-ethylthio-15-O-acetyl prostaglandin E₂ methyl ester--Method A

To a solution of 7.23 gm. of the methyl ester of 15-O-acetyl-prostaglandin A₂ in a mixture of 15 ml. ethanethiol, 15 ml. of tetrahydrofuran and 15 ml. of methanol is added 1.8 ml. of aqueous 5% sodium bicarbonate. The solution is stirred for twenty minutes and is evaporated in vacuo at 30° C. to a paste. To the paste is added 25 ml. ether and 10 ml. of water. The ether is separated and washed with brine. The aqueous layer is extracted with ether and the ether is washed with brine and the ether extracts are combined, dried with magnesium sulfate, and evaporated in vacuo to afford 8.375 gm. of 11-deoxy-11α-ethylthioprostaglandin E₂ methyl ester as an oil; λmax: 1740 cm⁻¹ (saturated ketone and esters), 1225 cm⁻¹ (acetate); [α]_(D) ²⁵ =-59.67° (C=0.481 chloroform).

EXAMPLE 3 Preparation of 11-deoxy-11α-methylthioprostaglandin E₂ --Method B

A solution of prostaglandin A₂ is treated as in Example 2 except that one equivalent of sodium bicarbonate in water is added before the addition of a catalytical amount of 5% aqueous sodium bicarbonate. In addition, the solution is acidified with a sodium biphosphate buffer prior to the extraction with ether to yield 11-deoxy-11α-methylthioprostaglandin E₂ after evaporation in vacuo of the organic solvents.

EXAMPLE 4 Conversion of 15-O-acetylprostaglandin A₂ methyl ester to prostaglandin A₂ methyl ester

To a 0° C. solution containing 12.15 gm. of 15-O-acetylprostaglandin A₂ methyl ester in 50 ml. of methanethiol and 100 ml. of methanol is added a small amount of potassium carbonate. The solution is stirred 30 minutes and 75 ml. of methanol and 8.55 gm. of potassium carbonate is added. The flask is tightly stoppered, secured with rubber bands and stirred at room temperature for two weeks. The solution is cooled in an ice bath and poured into 350 ml. of ether and 500 ml. of ice water. The aqueous layer is extracted with ether and the combined ether extracts are washed with brine and dried with magnesium sulfate. The ether is evaporated in vacuo and the residue is dissolved in 100 ml. of methanol and filtered through celite to remove stopcock crease. The methanol is evaporated in vacuo to afford 11.67 gm. of crude 11-deoxy-11α-methylthioprostaglandin A₂ methyl ester as an oil.

To a solution of 11.67 gm. of crude 11-deoxy-11α-methylthioprostaglandin A₂ methyl ester in a solution of 60 ml. tetrahydrofuran, 30 ml. of methanol and 25 ml. of iodomethane is added 70 ml. of a 5% aqueous sodium bicarbonate solution. The resulting solution is stirred vigorously and heated under reflux for four hours to form 11-deoxy-11α-dimethylsulfonium iodide prostaglandin A₂ methyl ester which is decomposed in solution to afford prostaglandin A₂ methyl ester.

The solution is cooled and added to 200 ml. of ether and 100 ml. of water. The aqueous layer is extracted with ether and the ether extracted are combined, washed with brine, dried with magnesium sulfate and evaporated in vacuo to afford 10.63 gm. of the crude prostaglandin A₂ methyl ester as an oil.

The oil is purified by dry column chromatography using acid washed silica gel. The material in methylenechloride is placed onto a 62"×3" flat diameter nylon tube containing the acid washed silica. The column is developed with ether and is then cut up into 10 equal sections. Sections 6, 7 and 8 are combined and the product is eluted from the silica gel with 20% methanol in chloroform.

Evaporation in vacuo of the solvents affords 8.64 gm. (80%) of prostaglandin A₂ methyl ester; λmax 1735 cm⁻¹, 1710 cm⁻¹, 1660 cm⁻¹, 3400 cm⁻¹ ; [α]_(D) ²⁵ =+137.5 (C=0.4, chloroform).

Elution of the material from sections 9 and 10 of the column in like fashion yields 1.2 gm. of the starting 15-O-acetyl prostaglandin methyl ester.

Substitution of ethanethiol for methanethiol in the above procedure results in the formation of 11-deoxy-11α-ethylthioprostaglandin A₂ methyl ester and 11-deoxy-11α-(ethyl methyl sulfonium iodide) prostaglandin A₂ methyl ester as intermediates in the preparation of prostaglandin A₂ methyl ester.

EXAMPLES 5-12

Treatment of the following A type prostaglandins with the following alkyl mercaptans in the manner of Example 2 (Method A) or Example 3 (Method B) is productive of the 11α-alkylthioprostaglandins (E type) of the table.

    __________________________________________________________________________     Example                                                                             Starting Prostaglandin                                                                     Alkyl Mercaptan                                                                         Method                                                                              Product 11α-alkylthio-prostaglandin       __________________________________________________________________________                                    E                                                5   15-O-acetyl ethanethiol                                                                             A    11-deoxy-11α-ethylthioprostaglandin                                      E.sub.2                                              prostaglandin                                                                  A.sub.2 methyl ester      methyl ester                                     6   prostaglandin A.sub.2                                                                      methanethiol                                                                            B    11-deoxy-11α-methylthioprostaglandin                                     E.sub.2                                          7   prostaglandin A.sub.2                                                                      ethanethiol                                                                             B    11-deoxy-11α-ethylthioprostaglandin                                      E.sub.2                                          8   prostaglandin A.sub.2                                                                      1-propanethiol                                                                          B    11-deoxy-11α-isopropylthioprostagland                                    in                                                                             E.sub.2                                          9   prostaglandin A.sub.1                                                                      methanethiol                                                                            B    11-deoxy-11α-methylthioprostaglandin                                     E.sub.1                                         10   prostaglandin A.sub.1                                                                      1-butanethiol                                                                           B    11-deoxy-11α-butylthioprostaglandin                                      E.sub.1                                         11   13,14-dihydroprosta-                                                                       methanethiol                                                                            B    11-deoxy-11α-methylthio-13,14-dihydro                                    -                                                    glandin A.sub.1           prostaglandin A.sub.1                           12   13,14-dihydroprosta-                                                                       1-propanethiol                                                                          B    11-deoxy-11α-propylthio-13,14-dihydro                                    -                                                    glandin A.sub.1           prostaglandin A.sub.1                           __________________________________________________________________________

EXAMPLE 13 Preparation of 11-deoxy-11α/β-15-O-acetylprostaglandin E₂ methyl ester

A solution of 5 g. of the methyl ester of 15-O-acetylprostaglandin A₂ in 10 ml. of thiolacetate acid is refluxed three hours. The solution is evaporated in vacuo at 45° C. and the residue is dissolved in benzene and the solution evaporated in vacuo to afford 5.18 g. of an oil. Thin layer chromatography indicates two compounds (epimers at C-11); λmax 1735 cm⁻¹ (saturated carbonyls), ##STR10##

EXAMPLES 14-16

Treatment of the following A type prostaglandins with thiolacetic acid by the procedure of Example 13 affords the 11-acetylthio E-type prostaglandins of the following table.

    ______________________________________                                         Ex-   Starting      Product                                                    ample Prostaglandin-A                                                                              11-acetylthio-prostaglandin E                              ______________________________________                                         14    Prostaglandin A.sub.2                                                                        11-deoxy-11α/β-acetylthioprosta-                                    glandin E.sub.2                                            15    Prostaglandin A.sub.1                                                                        11-deoxy-11α/β-acetylthioprosta-                                    glandin E.sub.1                                            16    13,14-dihydropros-                                                                           11-deoxy-11α/β- acetylthio-13,14-                     taglandin A.sub.1                                                        dihydroprostaglandin E.sub.1                                                   ______________________________________                                    

EXAMPLE 17 Preparation of 11-deoxy-11α-methyl-15-deoxy-15-methylprostaglandin E₂ methyl ester

To a solution, maintained at -10° C., of lithium dimethyl cuprate (4.87 g. cuprous iodide in 10 cc ether titrated with 2 M methyllithium until the solution is clear) is added dropwise a solution of 5.0 g. of the methyl ester of 15-O-acetyl-prostaglandin A₂ in 25 ml. of ether. The solution is stirred for 15 minutes and then is added to 200 ml. of saturated aqueous ammonium chloride. The aqueous solution is extracted with ether. The ether extracts are combined, washed with brine, dried with anhydrous magnesium sulfate and evaporated in vacuo to yield 4.65 g. of an oil. The oil is purified by silica gel chromatography with 3% ethyl acetate/benzene to afford 2.56 g. of the product as an oil; λmax 1740 cm⁻¹ (saturated carbonyls); [α]_(D) ²⁵ =-75.4° (C=0.5, chloroform) in addition is obtained 11-deoxy-11α-methyl-15-O-acetylprostaglandin A₂ methyl ester.

EXAMPLE 18 Preparation of 11-deoxy-11α-methyl-prostaglandin E₂ methyl ester

To a -20° C. solution of lithium dimethyl cuprate (prepared from 3.9 gm. cuprous iodide in ten ml. ether by titration with 1 M methyllithium until the resulting solution is clear) is added a solution of 3.36 g. of the methyl ester of prostaglandin A₂ (Example 4) in ten ml. of ether. The resulting solution is stirred forty-five minutes and then poured into 250 ml. of saturated ammonium chloride and stirred 15 minutes. The solution is extracted with ether and the ether extracts are combined, washed with brine, dried with anhydrous magnesium sulfate and evaporated in vacuo to afford 3.37 g. of an oil that is homogenous by thin layer chromatography; λmax 3400 cm⁻¹ (hydroxyl), 1740 (saturated carbonyls); [α]_(D) ²⁵ =-47.8° (C=0.5, chloroform).

EXAMPLE 19 Preparation of 11-deoxy-11α-vinylprostaglandin E₂ methyl ester

To a solution of (17.5 mM) lithium divinyl cuprate (prepared from 6.87 g. of the cuprous iodide-tributylphosphine complex and 17.5 ml. of 2 molar vinyllithium) in tetrahydrofuran at -78° C. is added a solution of 3 g. (8.65 mM) of prostaglandin A₂ methyl ester (Example 4) in 10 ml. of ether. The resulting viscous solution is diluted with 10 ml. of tetrahydrofuran and stirred at -78° C. for 60 minutes.

The solution is poured into 150 ml. of saturated aqueous ammonium chloride and stirred 1 hour at room temperature with 200 ml. of ether. The ether solution is separated and is extracted with water, washed with brine, dried with magnesium sulfate and evaporated in vacuo to yield 12.1 gm. of an oil.

The oil is triturated with methanol several times and the methanol washes are combined, filtered through celite and evaporated in vacuo to afford 5.9 g. of an oil; λmax: 3400 cm⁻¹ (hydroxyl), 1740 cm⁻¹ (saturated ketone and ester), 1635 cm⁻¹ (vinyl group); 970 cm⁻¹ (trans double bond), 920 cm⁻¹ (terminal vinyl).

EXAMPLES 20-28

Treatment of the A-type prostaglandin methyl esters listed in the table below with the indicated organolithium cuprates and by the indicated procedure is productive of the 11-alkyl or 11-alkenyl E-type prostaglandins of the table.

    __________________________________________________________________________                     Method of                                                                            Starting    Product 11α-alkyl/                     Example                                                                             Cuprate Reagent                                                                           Example                                                                              Prostaglandin Ester                                                                        alkenyl-11-deoxyprostaglandin-E              __________________________________________________________________________     20   diethylcopperlithium                                                                      18    prostaglandin A.sub.2 methyl                                                               11-deoxy-11α-ethylprostaglandin                                          E.sub.2                                                            ester       methyl ester                                 21   dipropylcopperlithium                                                                     18    prostaglandin A.sub.2 methyl                                                               11-deoxy-11α-propylprostaglandin                                         E.sub.2                                                            ester       methyl ester                                 22   diisopropylcopper-                                                                        18    prostaglandin A.sub.2 methyl                                                               11-deoxy-11α-isopropylprostaglandi                                       n                                                 lithium          ester       E.sub.2 methyl ester                         23   dipropenylcopper-                                                                         19    prostaglandin A.sub.2 methyl                                                               11-deoxy-11α-propenylprostaglandin          lithium          ester       E.sub.2 methyl ester                         24   dimethylcopperlithium                                                                     18    prostaglandin A.sub.2 methyl                                                               11-deoxy-11α-methylprostaglandin                                         E.sub.1                                                            ester       methyl ester                                 25   diethylcopperlithium                                                                      18    prostaglandin A.sub.1 methyl                                                               11-deoxy-11α-ethylprostaglandin                                          E.sub.1                                                            ester       methyl ester                                 26   divinylcopperlithium                                                                      19    prostaglandin A.sub.1 methyl                                                               11-deoxy-11α-vinylprostaglandin                                          E.sub.1                                                            ester       methyl ester                                 27   dipropenylcopper-                                                                         19    prostaglandin A.sub.1 methyl                                                               11-deoxy-11α-propenylprostaglandin          lithium          ester       E.sub.1 methyl ester                          28a divinylcopperlithium                                                                      19    13,14-dihydroprostag-                                                                      11-deoxy-11α-vinyl-13,14-dihydropr                                       o-                                                                 landin A.sub.1 methyl ester                                                                staglandin E.sub.1 methyl ester               28b divinylcopperlithium                                                                      19    prostaglandin A.sub.2 methyl                                                               11-deoxy-11α-vinylprostaglandin                                          E.sub.2                                                            ester       methyl ester                                 __________________________________________________________________________

EXAMPLE 29 Preparation of 11-deoxy-11α-methyl-13,14-dihydroprostaglandin E₁

To a suspension of 300 mg. of 5% rhodium-on-carbon in 10 ml. of ethylacetate is added a solution of 1.02 g. of 11-deoxy-11α-methylprostaglandin E₂ (Example 57) in 10 ml. ethylacetate. The resulting suspension is hydrogenated at 50 psi of hydrogen for 1 hour. The solution is filtered and the solvent is evaporated in vacuo to afford 1.04 g. of an oil. The oil is purified by dry column chromatography on a 29"×11/2" flat diameter nylon tube filled with acid washed silica gel. The column is developed with ethyl acetate/benzene/acetic acid (10:40:1) and the section corresponding to rf=0.38-0.53 was eluted with 20% methanol in chloroform to afford 542 mg. of the product as an oil; λmax 3400 cm⁻¹ (carboxyl and hydroxyl), 1740-1710 cm⁻¹ (carboxyl and saturated ketone); [α]_(D) ²⁵ =-49.5 (C=0.8, chloroform).

EXAMPLES 30-32

Treatment of the 11-deoxy-11-alkylprostaglandin E₂ methyl esters listed in the table below by the procedure of Example 29 yields the 11α-alkyl-11-deoxy-13,14-dihydro-prostaglandins E₁ of the table.

    ______________________________________                                                Starting       Product - 11α-alkyl-11-deoxy-                      Example                                                                               Prostaglandin-E.sub.2                                                                         13,14-dihydroprostaglandin-E.sub.1                       ______________________________________                                         30     11-deoxy-11α-ethyl-                                                                     11-deoxy-11α-ethyl-13,14-di-                              prostaglandin E.sub.2                                                                         hydroprostaglandin E.sub.1                               31     11-deoxy-11α-propyl-                                                                    11-deoxy-11α-propyl-13,14-di-                             prostaglandin E.sub.2                                                                         hydroprostaglandin E.sub.1                               32     11-deoxy-11-isopro-                                                                           11-deoxy-11α-isopropyl-13,14-                             pylprostaglandin E.sub.2                                                                      dihydroprostaglandin E.sub.1                             ______________________________________                                    

EXAMPLE 33 Preparation of 11-deoxy-11α-dicarboethoxymethyl-15-O-acetylprostaglandin E₂ methyl ester

To a solution of 97 mg. of the methyl ester of 15-O-acetyl-prostaglandin A₂ and 44 mg. of diethylmalonate in one ml. of tetrahydrofuran is added one drop of a 35% solution of benzyltrimethyl ammonium hydroxide in methanol. Two ml. of tetrahydrofuran is added and the solution is stirred overnight.

The solution is applied directly to a 2 mm silica-gel thin layer chromatography plate and developed with 20% ethyl acetate/benzene. The band corresponding to the product is scraped off of the plate and the product is isolated by elution off of the silica with 20% methanol/chloroform. The resulting solution is evaporated to afford 76 mg. of an oil; λmax 1740 cm⁻¹ (saturated carbonyls), 1225 cm⁻¹ (OAc), 1180 and 1020 cm⁻¹ (CO₂ Et), [α]_(D) ²⁵ =-60.98° (C=0.305, chloroform).

EXAMPLE 34 Preparation of 11-deoxy-11α-(α,α-dicarboethoxy)methylprostaglandin E₂

To a solution of 11-deoxy-11α-(α,α-dicarboethoxy)methyl-15-O-acetyl-prostaglandin E₂ methyl ester (Example 33) in methanol is added 2.2 equivalents of a 2.5 N aqueous sodium hydroxide solution. The resulting solution is stirred for 4 hours and then poured into water. Extraction of the aqueous solution with ether removes unreacted ester. The aqueous solution is acidified and extracted with ether. The ether solution is washed with brine, dried with magnesium sulfate and evaporated in vacuo to afford the product. Purification via dry column chromatography affords 11-deoxy-11α-(α,α-dicarboethoxy)methylprostaglandin E₂.

EXAMPLE 35 Preparation of 11-deoxy-11α-(α,α-dicarboxy)methylprostaglandin E₂

To the product derived from the treatment of 5.5 g. of 15-O-acetyl-prostaglandin A₂ methyl ester with diethylmalonate as per Example 33, in 25 ml. of tetrahydrofuran is added 30 ml. of 2.5 N aqueous sodium hydroxide. The solution is stirred overnight at room temperature, and is then heated at 80° C. for one hour. The cooled solution is poured into 50 cc ether and 100 cc water. The aqueous phase is separated and extracted with ether.

The aqueous phase is acidified with 6 N aqueous hydrochloric acid, saturated with sodium chloride and extracted with ether. The ether solution is dried with magnesium sulfate and evaporated in vacuo to afford 4.48 g. of nearly pure product; λmax 3400-2600 cm⁻¹ (carboxyl and hydroxyl groups), 1710-1750 cm⁻¹ (saturated ketone and carboxyls).

EXAMPLES 36-38

Treatment of the indicated A-type prostaglandins with the designated malonates by the procedure of Example 33 furnishes the products of the table.

    ______________________________________                                                Reagent    Starting     Product                                         Example                                                                               Malonate   Prostaglandin A                                                                             Prostaglandin E                                 ______________________________________                                         36     α-methyldi-                                                                         15-O-acetylprosta-                                                                          11-deoxy-11α-(α,α-                   ethylmalonate                                                                             glandin A.sub.2 methyl                                       dicarboethoxy                                                                                    ester        ethyl-15-O-acetyl-                                                             prostaglandin E.sub.2                                                          methyl ester                                    37     α-ethyldieth-                                                                       15-O-acetylprosta-                                                                          11-deoxy-11α-(α,α-                   ylmalonate glandin A.sub.2 methyl                                       dicarboethoxy                                                                                    ester        propyl-15-O-acetyl-                                                            prostaglandin E.sub.2                                                          methyl ester                                    38     diethyl-   prostaglandin A.sub.1                                                                       11-deoxy-11α-(α,α-                   malonate   methyl ester                                                 dicarboethoxy                                                                                                 methylprostaglandin                                                            E.sub.1 methyl ester                            ______________________________________                                    

EXAMPLE 39 Preparation of 11-deoxy-11α-nitromethyl-15-O-acetylprostaglandin E₂ methyl ester

To a solution of 15.1 g. of the methyl ester of 15-O-acetylprostaglandin A₂ in 15 ml. of tetrahydrofuran is added a solution of 15 ml. nitromethane containing 1 ml. of a 35% solution of triton B (benzyl-trimethyl ammonium hydroxide) in methanol. The solution is stirred for one hour and is then poured into a mixture of 75 ml. of water and 70 ml. of ether. One ml. of 6 N aqueous hydrochloric acid is added and the aqueous layer is extracted with ether. The ether extracts are combined, washed with brine, dried (anhydrous magnesium sulfate) and evaporated in vacuo to afford 17.5 g. of an oil that can be purified by dry column chromatography; λmax 1740 cm⁻¹ (saturated carbonyls), 1555 cm⁻¹ (NO₂), 1375 cm⁻¹ (NO₂), 1225 cm⁻¹ (OAc), [α]_(D) ²⁵ =-45.5, (C=0.530, chloroform).

EXAMPLES 40-45

Treatment of the indicated A-type prostaglandins with the designated nitroalkanes via the procedure of Example 39 is productive of the products of the following table.

    ______________________________________                                                                        Product-11-deoxy-                               Ex-   Reagent     Starting     11α-(nitroalkyl)-                         ample Nitroalkane Prostaglandin A                                                                             prostaglandin E                                 ______________________________________                                         40    nitroethane 15-O-acetylprosta-                                                                          11-deoxy-11α-(α-ni-                                   glandin A.sub.2 methyl                                                                      troethyl)-15-O-ace-                                               ester        tylprostaglandin E.sub.2                                                       methyl ester                                    41    2-nitropropane                                                                             15-O-acetylpros-                                                                            11-deoxy-11α-(α-                                      taglandin A.sub.2                                                                           nitro, α-methyl-                                            methyl ester ethyl)-15-O-acetyl-                                                            prostaglandin E.sub.2                                                          methyl ester                                    42    1-nitropropane                                                                             15-O-acetylpros-                                                                            11-deoxy-11α-(α-                                      taglandin A.sub.2                                                                           nitropropyl)-15-                                                  methyl ester O-acetylprostaglan-                                                            din E.sub.2 methyl ester                        43    nitromethane                                                                               prostaglandin A.sub.1                                                                       11-deoxy-11α-nitro-                                         methyl ester methyl prostaglan-                                                             din E.sub.1 methyl ester                        44    nitroethane prostaglandin A.sub.1                                                                       11-deoxy-11α-(α-                                      methyl ester nitroethyl)prosta-                                                             glandin E.sub.1 methyl                                                         ester                                           45    nitromethane                                                                               13,14-dihydropros-                                                                          11-deoxy-11α-nitro-                                         taglandin A.sub.1                                                                           methyl-13,14-dihy-                                                methyl ester droprostaglandin E.sub.1                                                       methyl ester                                    ______________________________________                                    

EXAMPLE 46 Preparation of 11-deoxyprostaglandin E₂ methyl ester

To a suspension of 300 mg. potassium carbonate in 30 ml. of methanol is added 11-deoxy-15-O-acetyl-prostaglandin E₂ methyl ester (Example 96) in one ml. of methanol. The solution is stirred for 48 hours and is then acidified with 6 N aqueous hydrochloric acid. The solution is diluted with water and extracted with ether. The ether solution is washed with brine, dried with magnesium sulfate and evaporated in vacuo to yield 540 mg. of crude product. The product is purified by dry column chromatography using acid washed silica gel and eluting with 20% ethylacetate in benzene; λmax: 3400 cm⁻¹ (hydroxy), 1735 cm⁻¹ (saturated ketone and ester).

EXAMPLE 47 Preparation of 11-deoxy-11α-nitromethyl prostaglandin E₂

To a solution of 11.54 g. of the methyl ester of 11-deoxy-11α-nitromethyl-15-O-acetyl-prostaglandin E₂ (Example 39) in 40 ml. of methanol is added 45 ml. of a 2.5 N sodium hydroxide solution and the resulting solution is stirred at room temperature for 2 hours. The solution is poured into 100 ml. of ether and 100 ml. of water. The aqueous layer is separated and extracted with ether. The aqueous layer is covered with ether and acidified with 23 ml. of 6 N aqueous hydrochloric acid. The acidic solution is saturated with sodium chloride and extracted with ether. The ether is dried with magnesium sulfate and evaporated in vacuo to give 10.3 g. of a viscous oil that is purified by dry column chromatography on acid washed silica gel; λmax 3600-3400 cm⁻¹ (hydroxyl and carboxyl), 1735 cm⁻¹ (saturated carbonyl), 1700 cm⁻¹ (carboxyl), 1550 cm⁻¹ (nitro); [α] _(D) ²⁵ =-41.5° (C=1.0, chloroform).

EXAMPLES 48-67

Saponification of the prostaglandin esters listed in the table by the indicated procedures yields the product prostaglandin acids of the following table.

    ______________________________________                                         Ex-   Starting Pros-                                                           ample taglandin Ester                                                                            Method of Product Acid                                       ______________________________________                                         48    Example 36  Example 34                                                                               11-deoxy-11α-(α,α-di-                                        carboethoxyethyl)pro-                                                          staglandin E.sub.2                                 49    Example 37  Example 34                                                                               11-deoxy-11α-(α,α-di-                                        carboethoxypropyl)-                                                            prostaglandin E.sub.2                              50    Example 38  Example 34                                                                               11-deoxy-11α-(α,α-di-                                        carboethoxymethyl)-                                                            prostaglandin E.sub.1                              51    Example 40  Example 47                                                                               11-deoxy-11α-(α -nitro-                                            ethyl)prostaglandin E.sub.2                        52    Example 41  Example 47                                                                               11-deoxy-11α-(α-nitro,                                             α-methylethyl)prosta-                                                    glandin E.sub.2                                    53    Example 42  Example 47                                                                               11-deoxy-11α-(α-nitro-                                             propyl)prostaglandin E.sub.2                       54    Example 43  Example 47                                                                               11-deoxy-11α-nitrome-                                                    thyl prostaglandin E.sub.1                         55    Example 44  Example 47                                                                               11-deoxy-11α-(α-nitro-                                             ethyl)prostaglandin E.sub.1                        56    Example 45  Example 47                                                                               11-deoxy-11α-nitrometh-                                                  yl-13,14-dihydroprosta-                                                        glandin E.sub.1                                    57    Example 18  Example 47                                                                               11-deoxy-11α-methyl-                                                     prostaglandin E.sub.2                              58    Example 19  Example 47                                                                               11-deoxy-11α-vinyl-                                                      prostaglandin E.sub.2                              59    Example 20  Example 47                                                                               11-deoxy-11α-ethyl-                                                      prostaglandin E.sub.2                              60    Example 21  Example 47                                                                               11-deoxy-11α-propyl-                                                     prostaglandin E.sub.2                              61    Example 22  Example 47                                                                               11-deoxy-11α-isopropyl-                                                  prostaglandin E.sub.2                              62    Example 23  Example 47                                                                               11-deoxy-11α-pentyl-                                                     prostaglandin E.sub.2                              63    Example 24  Example 47                                                                               11-deoxy-11α-methyl-                                                     prostaglandin E.sub.1                              64    Example 25  Example 47                                                                               11-deoxy-11α-ethylpros-                                                  taglandin E.sub.1                                  65    Example 26  Example 47                                                                               11-deoxy-11α-vinylpros-                                                  taglandin E.sub.1                                  66    Example 27  Example 47                                                                               11-deoxy-11α-propenyl-                                                   prostaglandin E.sub.1                              67    Example 28  Example 47                                                                               11-deoxy-11α-vinyl-13,14-                                                dihydroprostaglandin E.sub.1                        67a  Example 173 Example 47                                                                               11-deoxy-11α-(1-hydroxy-                                                 1-methylethyl)-prosta-                                                         glandin E.sub.2                                    ______________________________________                                    

EXAMPLE 68 Preparation of 11α/11β-cyano-11-deoxy-15-O-acetyl-prostaglandin E₂ methyl ester

To a solution of 9.4 g. of the methyl ester of 15-O-acetyl-prostaglandin-A₂ in a mixture of 10 ml. acetonecyanohydrin and 10 ml. methanol is added 1 ml. of 5% aqueous sodium carbonate. The resulting solution is refluxed overnight and after cooling, poured into cold water and extracted with ether. The combined ether extracts are washed with brine and dried with anhydrous magnesium sulfate and evaporated in vacuo to give 12.3 g. of an oil.

The material is redissolved in benzene and washed with water to remove acetonecyanohydrin. The benzene solution is dried with magnesium sulfate and evaporated in vacuo. The material is purified by dry column chromatography to afford 8.5 g. of subject compound as an oil; λmax 2220 cm⁻¹ (nitrile), 1735 cm⁻¹ (saturated carbonyls); [α]_(D) ²⁵ =-56.23°, (C=0.918, chloroform).

EXAMPLES 69-70

Treatment of the listed A-type prostaglandins by the procedure of Example 68 is productive of the 11α/β-cyano products of the following table.

    ______________________________________                                                 Starting      Product 11α/β-11-deoxy-                       Example Prostaglandin-A                                                                              prostaglandin-E                                          ______________________________________                                         69      prostaglandin A.sub.1                                                                        11α/β-cyano-11-deoxyprosta-                                         glandin E.sub.1                                          70      13,14-dihydropros-                                                                           11α/β-cyano-11-deoxy-13,14-                           taglandin A.sub.1                                                                            dihydroprostaglandin E.sub.1                             ______________________________________                                    

EXAMPLE 71 Preparation of 11α/β-cyano-11-deoxy-prostaglandin E₂

To a solution of 3 g. of the methyl ester of 11α/β-cyano-11-deoxy-15-O-acetyl-prostaglandin E₂ (Example 68) in 36 ml. of methanol is added 12 ml. of an aqueous saturated solution of sodium cyanide. The solution is stirred for 96 hours and then poured into 100 ml. of ether. 20 ml. of water is added and the ether is extracted twice with 15 ml. 5% aqueous sodium bicarbonate. The combined aqueous extracts are acidified to pH 3 with 6 N aqueous hydrochloric acid, saturated with sodium chloride, and extracted with ether. The ether extracts are combined, dried with magnesium sulfate, and evaporated in vacuo to afford 1.64 g. of 11α/β-cyano-11-deoxyprostaglandin E₂ as an oil; λmax 3400 cm⁻¹ (carboxyl, hydroxyl), 2220 cm⁻¹ (nitrile), 1735 cm⁻¹ (saturated carbonyl), 1700 cm⁻¹ (carboxyl).

The first ether extract is dried with magnesium sulfate and evaporated in vacuo to afford 0.8 g. of 11α/β-cyano-11-deoxyprostaglandin E₂ methyl ester as an oil; λmax 3400 cm⁻¹ (hydroxyl), 2220 cm⁻¹ (nitrile), 1735 cm⁻¹ (saturated carbonyl, ester).

EXAMPLES 72-73

Ester hydrolysis of the following compounds by this procedure of Example 71 yields the products of the following table.

    ______________________________________                                                Starting   Product 11α/β-deoxyprosta-                        Example                                                                               Prostaglandin                                                                             glandin E                                                    ______________________________________                                         72     Example 69 11α/β-cyano-11-deoxyprostaglan-                                     din E.sub.1                                                  73     Example 70 11α/β-cyano-11-deoxy-13,14-dihydro-                                 prostaglandin E.sub.1                                        ______________________________________                                    

EXAMPLE 74 Preparation of 11α/β-carboxamido-11-deoxy-15-O-acetyl prostaglandin E₂ methyl ester

To a solution of 5.04 g. of the methyl ester of 11α/β-cyano-11-deoxy-15-O-acetylprostaglandin E₂ (Example 68) in 10 ml. of ethanol, 10 ml. tetrahydrofuran and 10 ml. cyclohexene is added a solution consisting of 1.5 ml. of 25% methanolic tetramethylammonium hydroxide in 7.0 ml. of 30% hydrogen peroxide. The resulting solution is heated to 60° C. for one hour and then stirred 48 hours at room temperature. One drop of methyltricaprylammonium chloride is added and the solution is heated for 2 hours at 55° C. The solution is cooled and poured into 100 ml. ether and 100 ml. water. The aqueous layer is extracted with ether. The ether extracts are combined, dried with anhydrous magnesium sulfate and evaporated in vacuo to give 4.96 g. of an oil. The oil is purified by dry column chromatography on a 20"×1/4" column of silica gel and developed with 20% ethyl acetate in benzene to give 2.5 g. of the product carboxamide as an oil; λmax 3400-3600 cm⁻¹ (NH₂ of carboxamide), 1735 cm⁻¹ (saturated ketone and esters), 1675 cm⁻¹ (carboxamide carbonyl), 1620 cm⁻¹ (carboxamide), 1220 cm⁻¹ (acetate), 1180 cm⁻¹ (methyl ester); [α]_(D) ²⁵ =-114.7° (C=0.63, chloroform).

EXAMPLE 75 Preparation of 11α-carboxamido-11-deoxyprostaglandin E₂

To a solution of 1.41 g. of 11α/β-carboxamido-11-deoxy-15-O-acetylprostaglandin E₂ methyl ester (Example 74) in 5 ml. of methanol is added 2.8 ml. of a 2.5 N aqueous sodium hydroxide solution and 2.2 ml. of water. The solution is stirred overnight and poured into 50 ml. of ether and 50 ml. of water. The water is extracted with ether and the ether solutions are discarded. The aqueous solution is acidified to pH 2 with 6 N aqueous hydrochloric acid and saturated with sodium chloride. The aqueous solution is extracted with ether; the ethereal solution is dried with magnesium sulfate and the ether is evaporated in vacuo to yield 1.1 g. of the product as an oil; λmax: 3400 cm⁻¹ (carboxyl, hydroxyl, and amido hydrogens), 1740 cm⁻¹ (saturated ketone), 1710 cm⁻¹ (amide carbonyl); [α]_(D) ²⁵ =-25° (C=-76 chloroform, acetone).

EXAMPLE 76 Preparation of 11α-carboxy-11-deoxyprostaglandin E₂

To a solution of 737 mg. of 11α-carboxamido-11-deoxy-15-O-acetylprostaglandin E₂ methyl ester (Example 74) in 5 ml. of methanol is added dropwise 5 ml. of a 2.5 N aqueous sodium hydroxide solution. The solution is heated at 80° C. for two hours and an additional 5 ml. of 2.5 N aqueous sodium hydroxide then is added and the solution is heated at 80° C. for 15 hours. The solution is cooled and extracted with ether. The aqueous solution is acidified with 6 N aqueous hydrochloric acid and extracted with ether. The ethereal solution is washed with brine, dried with magnesium sulfate and evaporated in vacuo to yield 520 mg. of the crude product; λmax: 3400-2700 cm⁻¹ (hydroxyl and carboxyl groups), 1740-1710 cm⁻¹ (saturated ketone and carboxyl groups).

EXAMPLE 77-79

Hydrogenation of the listed prostaglandin E₂ derivative by the procedure of Example 29 furnishes the product 13,14-dihydroprostaglandin E₁ of the following table.

    ______________________________________                                                 Starting 11-substituted                                                                       Product 11-substituted-13,-                             Example prostaglandin E.sub.2                                                                         14-dihydroprostaglandin E.sub.1                         ______________________________________                                         77      Example 74     11α-carboxamido-11-deoxy-                                                13,14-dihydro-15-O-acetyl                                                      prostaglandin E.sub.1 methyl                                                   ester                                                   78      Example 75     11α-carboxamido-11-deoxy-                                                13,14-dihydroprostaglan-                                                       din E.sub.1                                             79      Example 76     11α-carboxy-11-deoxy-                                                    13,14-dihydroprostaglan-                                                       din E.sub.1                                             ______________________________________                                    

EXAMPLE 80 Preparation of 11-deoxy-11α-methyl-prostaglandin F₂α

To a -78° C. solution of 877 mg. 11-deoxy-11α-methylprostaglandin E₂ (Example 57) in 8 ml. tetrahydrofuran is added 9.8 ml. of 0.66 M lithium perhydro-9-b-boraphenalyl hydride in tetrahydrofuran. The solution is stirred for 30 minutes and then 15 ml. of water is added and the dry-ice bath is removed. The solution is poured into 20 ml. of water and extracted with ether. The combined ether extracts are washed with 5% sodium bicarbonate. The combined aqueous solutions are acidified with 6 N hydrochloric acid, saturated with sodium chloride and extracted with ether. The ether is dried with anhydrous magnesium sulfate and evaporated in vacuo to an oil; λmax 3400 cm⁻¹ (OH), 1700 cm⁻¹ (COOH); 420 Hz (2H) 15-H and 9β-H; [α]_(D) ²⁵ =+15° (C=0.4, chloroform).

EXAMPLE 81 Preparation of 11α-carboxamido-11-deoxyprostaglandin F₂α

To a -78° C. solution of 1.59 g. of the methyl ester of 11α-carboxamido-11-deoxy-15-O-acetyl-prostaglandin E₂ (Example 75) in 10 ml. tetrahydrofuran is added 7.35 ml. of 0.65 M lithium perhydro-9-b-boraphenalyl hydride in tetrahydrofuran. The solution is stirred for 60 minutes at -78°, then stirred at room temperature for 20 minutes. The tetrahydrofuran is evaporated in vacuo at 25° C. The residue is dissolved in 2 ml. methanol, 6 ml. water and 4 ml. of 2.5 N aqueous sodium hydroxide and stirred 3 hours at room temperature. The solution containing the 11-carboxamido-11-deoxy-15-O-acetyl-prostaglandin E₂ methyl ester is poured into 50 ml. of water and extracted with ether. The ether solution is washed with 5% aqueous sodium bicarbonate and combined with the aqueous solution. The combined aqueous solution is acidified with 6 N aqueous hydrochloric acid, saturated with sodium chloride, and extracted with ether. The ether is dried with magnesium sulfate and evaporated in vacuo to afford 1.48 g. of a viscous oil; λmax, 3400 cm⁻¹ (OH, NH₂, COOH), 1700 cm⁻¹ (COOH), 1660 cm⁻¹ (CONH₂); 405 Hz (15-H, 9β-H); [α]_(D) ²⁵ =+8.2° (C=0.65, chloroform.

EXAMPLES 82-89

Carbonyl reduction of the listed prostaglandin E derivatives by the procedure of the example designated furnishes the product prostaglandin F.sub.α, of the following table.

    ______________________________________                                               Starting 11-sub-                                                         Ex-   stituted prosta-     Product 11-substituted-                             ample glandin E   Method   prostaglandin F                                     ______________________________________                                         82    Example 21  81       11α-propyl-11-deoxypros-                                                 taglandin F.sub.2α                            83    Example 22  81       11α-isopropyl-11-deoxy-                                                  prostaglandin F.sub.2α                        84    Example 6   80       11α-methylthio-11-deoxy-                                                 prostaglandin F.sub.2α and                                               11α-methylthio-11-deoxy-                                                 prostaglandin-F.sub.2β                         85    Example 39  81       11α-nitromethyl-11-deoxy-                                                prostaglandin F.sub.2α and 11α-                                    nitromethyl-11-deoxy-                                                          prostaglandin F.sub.2β                         86    Example 35  80       11α-dicarboxymethyl-11-                                                  deoxyprostaglandin F.sub.2α                   87    Example 25  81       11α-ethyl-11-deoxyprosta-                                                glandin F.sub.2α                              88    Example 38  81       11α-(α,α-dicarboethoxy)-                                     methyl-11-deoxyprosta-                                                         glandin F.sub.1α                              89    Example 29  80       11α-methyl-11-deoxy-                                                     13,14-dihydroprostaglan-                                                       din F.sub.1α                                  ______________________________________                                    

EXAMPLE 90 Conversion of 11α-methyl-11-deoxyprostaglandin E₂ to 11α-methyl-11-deoxyprostaglandin F₂α and 11α-methyl-11-deoxyprostaglandin F₂β

To a solution of 11α-methyl-11-deoxyprostaglandin E₂ in methanol at 0° C. is added 1 molar equivalent of sodium borohydride. After 60 minutes the solution is poured into water, acidified to pH=3 with 6 N hydrochloric acid, saturated with sodium chloride and extracted with ether. The ethereal solution is dried with magnesium sulfate and the ether is evaporated in vacuo to afford a mixture of 11α-methyl-11-deoxyprostaglandin F₂α and 11α-methyl-11-deoxyprostaglandin F₂β.

EXAMPLES 91-95

Carbonyl reduction of the listed 11-substituted prostaglandin (E type) by the method of Example 90 is productive of the 11-substituted prostaglandins (F type) of the table.

    ______________________________________                                                Starting 11-substi-                                                                          Product 11-substituted prosta-                            Example                                                                               tuted prostaglandin                                                                          glandin Fα/β                                   ______________________________________                                         91     Example 29    11α-methyl-11-deoxy-13,14-di-                                            hydroprostaglandin F.sub.1α /F.sub.1β          92     Example 51    11α-(α-nitroethyl)-11-deoxy-                                       prostaglandin F.sub.2α /F.sub.2β               93     Example 65    11α-vinyl-11-deoxyprostaglan-                                            din F.sub.1α /F.sub.1β                         94     Example 75    11α-carboxamido-11-deoxypros-                                            taglandin F.sub.2α /F.sub.2β                   95     Example 66    11α-propenyl-11-deoxyprosta-                                             glandin F.sub.1α /F.sub.1β                     ______________________________________                                    

EXAMPLE 96 Preparation of 11-deoxyprostaglandin E₂ from 15-O-acetyl prostaglandin A₂ methyl ester

To a solution of 1.04 g. of 15-O-acetylprostaglandin A₂ methyl ester in 5 ml. of methanol is added a solution of 209 mg. of sodium cyanoborohydride in 2 ml. of methanol. The solution is adjusted to pH 3 with 2 N methanolic hydrogen chloride and maintained at this pH by addition of methanolic hydrochloric acid as necessary. After 90 minutes the solution is evaporated in vacuo, 5 ml. of water is added. The solution is saturated with sodium chloride and extracted with ether. The ether extracts are dried with magnesium sulfate and evaporated in vacuo to yield 1.02 g. of an oil consisting mainly of 11-deoxy-15-O-acetyl-prostaglandin F₂α /F₂β methyl esters.

To a solution of 900 mg. of the above mixture of 11-deoxy-15-O-acetyl-prostaglandin F₂α /F₂β methyl esters in 30 ml. of acetone at 0° C. is added 0.8 ml. of a standard chromic acid solution. The solution is stirred 10 minutes and poured into 70 ml. of ice and water. The aqueous solution is extracted with ether. The ether solution is dried with magnesium sulfate and evaporated in vacuo to afford 830 mg. of 11-deoxy-15-O-acetylprostaglandin E₂ methyl ester as an oil.

To a solution of 11-deoxy-15-O-acetyl-prostaglandin E₂ methyl ester in methanol is added 4 equivalents of 2.5 N aqueous sodium hydroxide. The solution is stirred for 3 hours, poured into water, saturated with sodium chloride and acidified with 6 N aqueous hydrochloric acid to pH 3.

The acidic solution is extracted with ether. The ethereal extracts are dried with magnesium sulfate and evaporated in vacuo to afford 11-deoxyprostaglandin E₂ ; λmax: 3400-2700 cm⁻¹ (carboxyl and hydroxyl), 1745-1710 cm⁻¹ (saturated ketone and carboxyl groups).

EXAMPLE 97 Epimerization of 11-deoxyprostaglandin E₂ methyl ester

To a solution of 24 mg. of 11-deoxyprostaglandin E₂ methyl ester (Example 46) in 0.5 ml. of methylenechloride at -5° C. is added 15 μl of triethylamine followed by 28 mg. of methanesulfonic acid anhydride in 0.5 cc methylenechloride. The solution is stirred at -5° C. for 30 minutes and then all solvents are removed in vacuo.

The residue is dissolved in 5 ml. of ether and the ether solution is added to a flask containing 245 mg. of tetraethylammonium formate. The ether is evaporated in vacuo at -5° C. and replaced by 2 cc of dry acetone. The solution is maintained at 10° C. for 18 hours. The acetone is removed in vacuo and the residue is dissolved in 10 cc ether. The ether solution is washed with 5 ml. of 5% aqueous sodium bicarbonate solution and 5 ml. of brine. The ether solution is dried with magnesium sulfate and the ether evaporated in vacuo to yield 26.7 mg. of 11-deoxy-15R-O-formylprostaglandin E₂ methyl ester as an oil.

Treatment of a solution of the 11-deoxy-15R-O-formylprostaglandin E₂ methyl ester in 0.5 ml. of methanol with a crystal of p-toluenesulfonic acid overnight yields 15R-11-deoxyprostaglandin E₂ methyl ester as an oil that chromatographs slightly ahead of the starting 15S-11-deoxyprostaglandin E₂ methyl ester on silica gel. The residue also contains some of the starting 15S material.

EXAMPLE 98 Racemization of 15S-11-deoxyprostaglandin E₂ methyl ester

To 13 mg. of 15S-11-deoxyprostaglandin E₂ methyl ester (Example 46) is added a solution of 5 mg. potassium carbonate in 0.5 ml. of 97% formic acid. The solution is stirred under nitrogen for 60 minutes. Benzene is added and the solution is evaporated in vacuo.

The residue is placed on a 2 mm silica gel plate and developed with 20% ethylacetate in benzene. The area corresponding to rf=0.45-0.65 is removed and the compound is eluted off of the silica-gel with 20% methanol in chloroform. The silica-gel is filtered and the organic solvents are evaporated in vacuo to yield 9 mg. of a mixture of 11-deoxy-15-O-formylprostaglandin E₂ methyl ester and the corresponding 15R epimer.

The mixture of 15-O-formyl compounds is dissolved in 1 ml. of methanol and one small crystal of p-toluenesulfonic acid is added. The solution is stirred overnight to afford approximately a 1:1 mixture of 15S-11-deoxyprostaglandin E₂ methyl ester and 15R-11-deoxyprostaglandin E₂ methyl ester.

Thin layer chromatography on silica-gel indicates the newly formed epimer (15R) is slightly less polar than the starting (15S) epimer.

EXAMPLE 99 Conversion of 11-deoxy-11α-nitromethylprostaglandin E₂ to 11-deoxy-11-formylprostaglandin E₂

A solution of 208 mg. 11-deoxy-11α-nitromethylprostaglandin E₂ (Example 47) in 5.5 ml. of 0.21 N aqueous sodium hydroxide is added dropwise to a very rapidly stirred solution of 0.5 ml. 6 N hydrochloric acid in 5 ml. methanol. The solution is poured into 30 ml. of ether and 25 ml. of brine is added. The ether extracts are washed with brine, dried with magnesium sulfate and evaporated in vacuo to afford 167 mg. of a viscous oil. Purification by dry column chromatography using ethyl acetate/benzene/acetic for development followed by elution from the silica-gel with 20% methanol/chloroform affords the product as a mixture of 11-formyl-11-deoxyprostaglandin E₂ and the corresponding acetyl, 11-dimethoxymethyl-11-deoxyprostaglandin E₂.

EXAMPLE 100 Conversion of 11-deoxy-11α-(α,α-dicarboxy)methylprostaglandin E₂ to 11-deoxy-11α-carboxymethylprostaglandin E₂

A solution of 11-deoxy-11α-(α,α-dicarboxy)methylprostaglandin E₂ (Example 35) is dissolved in xylene and heated until carbon dioxide evolution begins. The solution is maintained at that temperature until the starting material has been consumed (thin layer chromatography evidence). The xylene solution is evaporated in vacuo to afford the product.

EXAMPLE 101 Preparation of 11α-(β-dimethylaminoethylthio)-11-deoxy-15-O-acetyl-prostaglandin A₂ methyl ester

A solution of 164 mg. of 2-diethylaminoethanethiol hydrochloride in 1 ml. of methanol containing 6 drops of a 5% aqueous sodium bicarbonate solution (pH˜8) is added to a solution of 104 mg. 15-O-acetylprostaglandin A₂ methyl ester in 1 ml. of methanol. The solution is stirred twenty minutes and then evaporated in vacuo to a paste. The paste was dissolved in 20 ml. of ether and 20 ml. of water. A small amount of sodium chloride is added to break up the emulsion formed. The aqueous layer is extracted with ether. The ether extracts are dried with magnesium sulfate and the ether is evaporated in vacuo to afford the product as an oil; λmax: 1745 cm⁻¹ (saturated ketone and esters), 1240 cm⁻¹ (acetate).

EXAMPLE 102 Preparation of 11-mercapto-15-O-acetylprostaglandin F₂α methyl ester

To a solution of 1.0 g. of 11-acetylthio-11-deoxy-15-O-acetyl prostaglandin A₂ methyl ester in 4 ml. of tetrahydrofuran maintained at -78° C. is added a solution of 0.65 M lithium perhydro-9-b-boraphenalyl hydride in tetrahydrofuran. The solution is stirred at -78° C. for 1 hour. The solution is then poured into 50 ml. of ether and 50 ml. of water and the aqueous layer is saturated with sodium chloride.

The aqueous layer is extracted with ether and the combined ether extracts are dried with magnesium sulfate and the ether is evaporated in vacuo to afford 1.7 g. of residue. Trituration of the residue with benzene/hexane followed by filtration and evaporation of the organic solvents affords 1.1 g. of crude product. The material is purified by partition chromatography to afford 150 mg. of 11-mercapto-11-deoxy-15-O-acetyl prostaglandin F₂α methyl ester.

EXAMPLE 103 Preparation of 1 20-ethyl prostaglandin A₂

A solution of 1 20-ethyl-9-oxo-11,15(S)-bis-(tetrahydropyran-2-yloxy)-5-cis-13-trans-prostadienoic acid [Pat. No. 2,150,361 (West Germany, 1972)] in tetrahydrofuran containing 1.5 N hydrochloric acid is kept at ambient temperature for 70 hours. The solution is flooded with saturated sodium chloride and extracted several times with ether. The combined extracts are washed with water, dried with anhydrous magnesium sulfate and taken to dryness to afford the subject compound.

EXAMPLES 104-114

The prostaglandins E of the table below when treated in the manner of Example 103 furnish the corresponding prostaglandins A.

    __________________________________________________________________________     Example                                                                             Starting Prostaglandin E                                                                          Product Prostaglandins A                               __________________________________________________________________________     104  l-17,20-tetranor-16-m-chlorophenoxy-                                                              l-17,20-tetranor-16-m-chlorophenoxy-                        prostaglandin-E.sub.2                                                                             prostaglandin-A.sub.2                                  105  l-17,20-tetranor-16-phenoxyprosta-                                                                l-17,20-tetranor-16-phenoxyprosta-                          glandin-E.sub.2    glandin-A.sub.2                                        106  l-17,20-tetranor-16-p-fluorophenoxy-                                                              l-17,20-tetranor-16-p-fluorophenoxy-                        prostaglandin-E.sub.2                                                                             prostaglandin-A.sub.2                                  107  l-17,20-tetranor-16-m-trifluoro-                                                                  l-17,20-tetranor-16-m-trifluoro-                            methylphenoxyprostaglandin-E.sub.2.sup.a                                                          methylphenoxyprostaglandin-A.sub.2                     108  l-20-methylprostaglandin-E.sub.2.sup.b                                                            l-20-methylprostaglandin-A.sub.2                       109  l-prostaglandin-E.sub.3 -E.J. Corey, et al.                                                       l-prostaglandin-A.sub.3                                     Journ. Amer. Chem. Soc., 93, 1490                                              (1971)                                                                    110  dl-prostaglandin-E.sub.2                                                                          dl-prostaglandin-A.sub.2                                    E.J. Corey, et al., Journ. Amer.                                               Chem. Soc., 91, 5675 (1969)                                               111  dl-17,20-tetranor-16-m-chlorophenoxy-                                                             dl-17,20-tetranor-16-m-chlorophenoxy-                       prostaglandin-E.sub.2.sup.c                                                                       prostaglandin-A.sub.2                                  112  dl-17,20-tetranor-16-phenoxyprosta-                                                               dl-17,20-tetranor-16-phenoxyprosta-                         glandin-E.sub.2.sup.c                                                                             glandin-A.sub.2                                        113  dl-17,20-tetranor-16-p-fluoro-                                                                    dl-17,20-tetranor-16-p-fluorophenoxy-                       phenoxyprostaglandin-E.sub.2.sup.c                                                                prostaglandin-A.sub.2                                  114  dl-17,20-tetranor-16-m-trifluoromethyl-                                                           dl-17,20-tetranor-16-m-trifluoromethyl-                     prostaglandin-E.sub.2.sup.c                                                                       phenoxyprostaglandin-A.sub.2                           __________________________________________________________________________      References:                                                                    .sup.a D. Binder et al., Prostaglandins, Vol. 6, No. 1, 87 (1974).             .sup.b D. van Dorp, Annal of the New York Academy of Sciences, Volume 180      181 (1971).                                                                    .sup.c Netherlands Patent No. 7,206,361, May 11, 1971.                   

EXAMPLES 115-129

Treatment of the A type prostaglandins, listed in the table below, with the listed alkyl mercaptans in the manner of Example 2 (method A) or Example 3 (method B) is productive of the 11α-alkylthioprostaglandins of the table.

    __________________________________________________________________________          Starting   Alkyl         Product 11α-alkylthio-                     Example                                                                             Prostaglandin A                                                                           Reagent Mercaptan                                                                       Method                                                                              11-deoxyprostaglandin E                          __________________________________________________________________________     115  1-prostaglandin-A.sub.3                                                                   Ethanethiol                                                                             B    l-11-deoxy-11α-ethylthioprostaglandin-          (Example 109)            E.sub.3                                          116  l-15-epiprosta-                                                                           Methanethiol                                                                            B    l-11-deoxy-11α-methylthio-15-epi-prost                                   a-                                                    glandin-A.sub.2          glandin-E.sub.2                                  117  l-15-epi-O-acetyl-                                                                        1-propanethiol                                                                          A    l-11-deoxy-11α-(1-propylthio)-15-               prostaglandin-A.sub.2    epi-O-acetylprostaglandin-E.sub.2                     methyl ester             methyl ester                                     118  dl-prostaglandin-A.sub.1                                                                  1-butanethiol                                                                           B    dl-11-deoxy-11α-butylthioprostaglandin                                   E.sub.1                                          119  l-15-methylprosta-                                                                        methanethiol                                                                            B    l-11-deoxy-11α-methylthioprosta-                glandin-A.sub.1 methyl   glandin-E.sub.1 methyl ester                          ester                                                                     120  l-15-methylprosta-                                                                        ethanethiol                                                                             B    l-11-deoxy-11α-ethylthio-15-methyl-             glandin-A.sub.2 methyl   prostaglandin-E.sub.2 methyl ester                    ester                                                                     121  l-16,16-dimethyl-                                                                         1-propanethiol                                                                          B    l-11-deoxy-11α-propylthio-16,16-di-             prostaglandin-A.sub.2    methylprostaglandin-E.sub.2                      122  l-16(S)-methyl-                                                                           ethanethiol                                                                             B    l-11-deoxy-11α-ethylthio-16(S)-methyl-          prostaglandin-A.sub.2    prostaglandin-E.sub.2                            123  l-16,16-difluoro-                                                                         Methanethiol                                                                            B    l-11-deoxy-11α-methylthio-16,16-                prostaglandin-A.sub.2    difluoroprostaglandin-E.sub.2                    124  l-16-fluoroprosta-                                                                        Methanethiol                                                                            B    l-11-deoxy-11α-methylthio-16-                   glandin-A.sub.2          fluoroprostaglandin-E.sub.2                      125  l-20-ethylprosta-                                                                         Methanethiol                                                                            B    l-11-deoxy-11α-methylthiol-20-                  glandin-A.sub.2 (EX.103) ethylprostaglandin-E.sub.2                       126  dl-17,20-tetranor-                                                                        Ethanethiol                                                                             B    dl-11-deoxy-11α-ethylthio-17,20-                16-p-fluoro-             tetranor-16-p-fluorophenoxy-                          phenoxyprostaglan-       prostaglandin-E.sub.2                                 din-A.sub.2 (Ex. 113)                                                     127  dl-17,20-tetranor-                                                                        Methanethiol                                                                            B    dl-11-deoxy-11α-methylthio-17,20-               16-m-trifluoro-          tetranor-16-m-trifluoromethyl-                        methylphenoxy-           phenoxyprostaglandin-E.sub.2                          prostaglandin-A.sub.2                                                          (Ex. 114)                                                                 128  l-17,20-tetranor-                                                                         Butanethiol                                                                             B    l-11-deoxy-11-α-butylthio-17,20-tetra-          16-m-trifluoro-          nor-16-m-trifluoromethylphenoxy-                      methylphenoxy-           prostaglandin-E.sub.2                                 prostaglandin-A.sub.2                                                          (EX. 107)                                                                 129  l-17,20-tetranor-                                                                         Methanethiol                                                                            B    l-11-deoxy-11α-methylthio-17,20-                16-m-chloro-             tetranor-16-m-chlorophenoxy-                          phenoxyprosta-           prostaglandin-E.sub.2                                 glandin-A.sub.2                                                                (EX. 104)                                                                 __________________________________________________________________________

EXAMPLES 130-140

Treatment of the following prostaglandins A₁, listed in the table below, with the following indicated organic lithium cuprate reagents in the manner of Examples 18 or 19 as indicated is productive of the 11-alkyl, or 11-alkenyl prostaglandin E type.

    __________________________________________________________________________     Ex- Starting   Cuprate      Product                                            ample                                                                              Prostaglandin A                                                                           Reagent Method                                                                              11-Substituted-11-deoxyprostaglandin               __________________________________________________________________________                                 E                                                  130 l-prostaglandin-A.sub.3                                                                   dimethyl copper                                                                        18   l-11-deoxy-11α-11α-methylprostagla                                 ndin-E.sub.3                                           (Example 109)                                                                             lithium                                                         131 l-prostaglandin-A.sub.2                                                                   dimethyl copper                                                                        18   l-11-deoxy-11α-methylprostaglandin-E.sub                                 .2                                                     methyl ester                                                                              lithium      methyl ester                                       132 l-15-epiprosta-                                                                           diethyl copper                                                                         18   l-11-deoxy-11α-ethyl-15-epi-prosta-              glandin-A.sub.2                                                                           lithium      glandin-E.sub.2                                    133 l-prostaglandin-A.sub.2                                                                   diphenylcopper                                                                         19   dl-11-deoxy-11α-phenylprostaglandin                                      E.sub.2                                                methyl ester                                                                              lithium      and dl-11-deoxy-11β-phenylprostaglandin-                                  E.sub.2 methyl ester                               134 l-15-methylprosta-                                                                        dimethyl copper                                                                        19   1-deoxy-11α-methyl-15-methylprostaglandi                                 n-                                                     glandin-A.sub.2                                                                           lithium      E.sub.2 methyl ester                                   methyl ester                                                               135 l-16,16-dimethyl-                                                                         dimethyl copper                                                                        18   l-11-deoxy-11α-methyl-16,16-dimethyl-            prostaglandin-A.sub.1                                                                     lithium      prostaglandin-E.sub.1 methyl ester                     methyl ester                                                               136 l-16(S)-methyl-                                                                           divinylcopper                                                                          19   l-11-deoxy-11α-vinyl-16(S)-methylprosta-         prostaglandin-A.sub.2                                                                     lithium      glandin-E.sub.2                                    137 l-16-fluoroprosta-                                                                        di-(1-butenyl)-                                                                        19   l-11-deoxy-11α-(1-butenyl)-16-fluoro-            glandin-A.sub.1                                                                           copper lithium                                                                              prostaglandin-E.sub.2                              Ex- Starting   Cuprate Method                                                                              Product                                            ample                                                                              Prostaglandin                                                                             Reagent of Ex.                                                                              11-Substituted-11-deoxyprostaglandin-E             __________________________________________________________________________     138 l-20-ethylprosta-                                                                         dipropentyl-                                                                           19   l-11-deoxy-11α-propenyl-20-ethylprosta-          glandin-A.sub.2 (Ex. 103)                                                                 copper lithium                                                                              glandin-E.sub.2                                    139 l-17,20-tetranor-                                                                         dimethyl-                                                                              18   l-11-deoxy-11α-methyl-17,20-tetranor-m-          16-m-trifluoro-                                                                           copper lithium                                                                              trifluoromethylphenylprostaglandin-E.sub.2             phenoxyprostaglan-                                                             din-A.sub.2 (Ex. 114)                                                      140 l-17,20-tetranor-                                                                         dimethyl-                                                                              18   l-11-deoxy-11α-methyl-17,20-tetranor-16-         16-m-chlorophen-                                                                          copper lithium                                                                              m-chlorophenoxyprostaglandin-E.sub.2                   oxyprostaglandin-                                                              A.sub.2 (Ex. 104)                                                          140A                                                                               l-17,20-tetranor-                                                                         divinyl-                                                                               19   l-11-deoxy-11α-vinyl-17,20-tetranor-16-          16-m-trifluoro-                                                                           copper lithium                                                                              m-trifluoromethylphenoxyprostaglandin-                 methylphenoxyprosta-                                                           glandin-A.sub.2 (Ex. 114)                                                  140B                                                                               l-17,20-tetranor-16-                                                                      divinyl-                                                                               19   l-11-deoxy-11α-vinyl-17,20-tetranor-16-          m-chlorophenoxy-                                                                          copper lithium                                                                              m-chlorophenoxyprostaglandin-E.sub.2                   prostaglandin-A.sub.2                                                          (Ex. 104)                                                                  140C                                                                               l-17,20-tetranor-16-                                                                      divinyl-                                                                               19   l-11-deoxy-11α-vinyl-17,20-tetranor-16-          p-fluorophenoxy-                                                                          copper lithium                                                                              p-fluorophenoxyprostaglandin-E.sub.2                   prostaglandin-A.sub.2                                                          (Ex. 106)                                                                  140D                                                                               l-16,16-dimethyl-                                                                         divinyl-                                                                               19   l-11-deoxy-11α-vinyl-16,16-dimethyl-             prostaglandin-A.sub.2                                                                     copper lithium                                                                              prostaglandin-E.sub.2                              __________________________________________________________________________

EXAMPLES 141-145

Reduction of the 11-deoxy-11-alkylprostaglandins E listed in the table below by the procedure of Example 29 yields the 11-alkyl-11-deoxy-13,14-dihydroprostaglandins-E₁ of the table.

    __________________________________________________________________________     Example                                                                             Starting 11α-alkyl prostaglandin E                                                        Product 13,14-dihydroprostaglandin                       __________________________________________________________________________                           E.sub.1                                                  141  l-11-deoxy-11α-methyl-15-methyl-                                                          l-11-deoxy-11α-methyl-13,14-dihydro-15-methyl-          prostaglandin-E.sub.2 methyl ester                                                              prostaglandin-E.sub.1 methyl ester                            (EX. 134)                                                                 142  l-11-deoxy-11α-ethyl-15-epi-                                                              l-11-deoxy-11α-ethyl-15-epi-13,14-dihydro-              prostaglandin-E.sub.2 (EX. 132)                                                                 prostaglandin-E.sub.1                                    143  l-11-deoxy-11α-methyl-16,16-di-                                                           l-11-deoxy-11α-methyl-13,14-dihydro-16,16-di-           methylprostaglandin-E.sub.1 methyl                                                              methylprostaglandin-E.sub.1 methyl ester                      ester (EX. 135)                                                           144  l-11-deoxy-11α-phenylprostaglandin-                                                       l-11-deoxy-11α-methyl-13,14-dihydroprostagland                           in-                                                           E.sub.2 methyl ester (EX. 133)                                                                  E.sub.1 methyl ester                                     145  l-11-deoxy-11α-methyl-17,20-tetra-                                                        l-11-deoxy-11α-methyl-13,14-dihydro-17,20-tetr                           a-                                                            nor-16-m-trifluoromethylphenoxy-                                                                nor-16-m-trifluoromethylphenoxyprostaglandin-E.sub.1          prostaglandin-E.sub.2 (EX. 139)                                           __________________________________________________________________________

EXAMPLES 146-157

Treatment of the 11-deoxy-11α/β-acetylmercaptoprostaglandin E of the following table by the method of Example 236 is productive of the 11-deoxy-11α-mercaptoprostaglandin F of the table.

    __________________________________________________________________________          Starting 11-deoxy-11α/β-                                       Example                                                                             acetylmercaptoprostaglandin E                                                                 Product 11-deoxy-11α-mercaptoprostaglandin                               Fα                                                   __________________________________________________________________________     146  223            l-11-deoxy-13,14-dihydro-11α-mercaptoprostagland                         in-                                                                            F.sub.1 α                                            147  224            l-11-deoxy-11α-mercaptoprostaglandin-F.sub.3                             α                                                    148  226            l-11-deoxy-15-epi-11α-mercaptoprostaglandin-F.su                         b.2 α                                                149  227            dl-11-deoxy-11α-mercaptoprostaglandin-F.sub.1                            α                                                    150  228            l-11-deoxy-16,16-dimethyl-11α-mercaptoprostaglan                         din-                                                                           F.sub.1 α                                            151  229            1-11-deoxy-16,16-dimethyl-11α-mercaptoprostaglan                         din-                                                                           F.sub.2 α                                            152  230            l-11-deoxy-16(S)-methyl-11α-mercaptoprostaglandi                         n-F.sub.2 α                                          153  231            l-11-deoxy-16-fluoro-11α-mercaptoprostaglandin-F                         .sub.2 α                                             154  232            l-11-deoxy-20-methyl-11α-mercaptoprostaglandin-F                         .sub.2 α                                             155  233            dl-11-deoxy-17,20-tetranor-11α-mercapto-16-m-tri                         -                                                                              fluoromethylphenoxyprostaglandin-F.sub.2 α           156  234            l-11-deoxy-16-p-fluorophenoxy-17,20-tetranor-11α                         -                                                                              mercaptoprostaglandin-F.sub.2 α                      157  235            l-16-m-chlorophenoxy-11-deoxy-17,20-tetranor-11α                         -                                                                              mercaptoprostaglandin-F.sub.2 α                      __________________________________________________________________________

EXAMPLES 158-167

Treatment of the following A type prostaglandins by the procedure of Example 68 is productive of the 11α and 11β-cyano prostaglandins of the table. The 11α and 11β-epimers are separable from each other by chromatographic procedures (see Example 212).

    __________________________________________________________________________     Example                                                                             Starting Prostaglandin A                                                                       Product 11α/β-cyano-11-deoxyprostaglandin                           E                                                         __________________________________________________________________________     158  l-prostaglandin-A.sub.3 (EX. 109)                                                              l-11-deoxy-11α-cyanoprostaglandin-E.sub.3 and                            l-11-deoxy-11β-cyanoprostaglandin-E.sub.3            159  dl-prostaglandin-A.sub.2                                                                       dl-11-deoxy-11α-cyanoprostaglandin-E.sub.2                               and                                                                            dl-11-deoxy-11β-cyanoprostaglandin-E.sub.2           160  l-15-methylprostaglandin-A.sub.2                                                               l-11-deoxy-11α-cyano-15-methylprostaglandin-E.s                          ub.2                                                           methyl ester    and l-11-deoxy-11β-cyano-15-methylprosta-                                 glandin-E.sub.2 methyl esters                             161  l-16,16-dimethylprostaglandin-A.sub.2                                                          l-11-deoxy-11α-cyano-16,16-dimethylprosta-                               glandin-E.sub.2 and l-11-deoxy-11β-cyano-16,16-d                          i-                                                                             methylprostaglandin-E.sub.2                               162  l-16(S)-methylprostaglandin-A.sub.2                                                            l-11-deoxy-11α-cyano-16(S)-methylprostaglandin-                          E.sub.2 and l-11-deoxy-11β-cyano-16(S)-methyl-                            prostaglandin-E.sub.2                                     163  l-16,16-difluoroprostaglandin-A.sub.2                                                          l-11-deoxy-11α-cyano-16,16-difluoroprostaglandi                          n-                                                                             E.sub.2 and l-11-deoxy-11β-cyano-16,16-difluoro-                          O                                                                              prostaglandin-E.sub.2                                     164  l-16-fluoroprostaglandin-A.sub.2                                                               l-11-deoxy-11α-cyano-16-fluoroprostaglandin-E.s                          ub.2                                                                           and d-11-deoxy-11β-cyano-16-fluoroprosta-                                 glandin-E.sub.2                                           165  dl-17,20-tetranor-16-p-fluoro-                                                                 dl-11-deoxy-11α-cyano-17,20-tetranor-16-p-fluor                          o-                                                             phenoxyprostaglandin-A.sub.2                                                                   phenoxyprostaglandin-E.sub.2 and dl-11-deoxy-11β                          -                                                              methyl ester (EX. 113)                                                                         cyano-17,20-tetranor-16-p-fluorophenoxyprosta-                                 glandin-E.sub.2                                           166  l-17,20-tetranor-16-m-trifluoro-                                                               l-11-deoxy-11αcyano-17,20-tetranor-16-m-tri-             methylphenoxyprostaglandin-A.sub.2                                                             fluoromethylphenoxyprostaglandin-E.sub.2 and l-11-             (EX. 107)       deoxy-11β-cyano-17,20-tetranor-16-m-trifluoro-                            methylphenoxyprostaglandin-E.sub.2                        167  l-17,20-tetranor-16-m-chloro-                                                                  l-11-deoxy-11α-cyano-17,20-tetrano-16-m-chloro-                          N                                                              phenoxyprostaglandin-A.sub.  2                                                                 phenoxyprostaglandin-E.sub.2 and l-11-deoxy-11β-                          O                                                              (EX. 104)       cyano-17,20-tetranor-16-m-chlorophenoxyprosta-                                 glandin-E.sub.2                                           __________________________________________________________________________

EXAMPLE 168 Preparation of 11-deoxy-11α-hydroxymethyl-15-O-acetyl prostaglandin-E₂ methyl ester, 11-deoxy-11β-hydroxymethyl-15-O-acetyl prostaglandin-E₂ methyl ester, and 8-iso-11-deoxy-11α-hydroxymethyl-15-O-acetyl prostaglandin-E₂ methyl ester

A solution of 30 gm. (77 mmol) of 15-O-acetylprostaglandin-A₂ methyl ester benzophenone in 4 l. of methanol is irradiated with a Hanovia 450 medium pressure lamp thru a pyrex immersion well for 5 hours at ambient temperature. The solvent is removed in vacuo and the residue is triturated 10 times with 100 ml. of petroleum ether (30°-60° C.). The insoluble material (35 gm.) is chromatographed on a 4 foot×6 inch (flat diaeter) nylon column of acid washed silica gel using ethyl acetate/benzene (1:3). The column is developed several times and fractions are collected.

From the chromatography is obtained 6 gm. of 11-deoxy-11β-hydroxymethyl-15-O-acetylprostaglandin-E₂ methyl ester: νmax 3400, 1735 cm⁻¹ ; [α]_(D) ²⁵ =-86°. (c=0.2, MeOH); CD:Δε=-3.2 at 293 nm. There is obtained both 8-iso and 8-normal-11-deoxy-11α-hydroxymethyl-15-O-acetylprostaglandin-E₂ methyl ester. These two products are further purified by dry column chromatography to give pure 11-deoxy-11α-hydroxymethyl-15-O-acetylprostaglandin-E₂ methyl ester: νmax -2.8 3400, 1735 cm⁻¹, [α]_(D) ²⁵ =-40°. (c=0.2, MeOH); CD:Δε=-at 293 nm; and pure 8-iso-11-deoxy-15-O-acetylprostaglandin-E₂ methyl ester: νmax 3400, 1735 cm⁻¹ ; [α]_(D) ²⁵ =+25° (c=0.2, MeOH); CD:Δε=+2.04 at 293 nm.

EXAMPLES 169-182

Treatment of the following A type prostaglandins with the indicated alcohols in the manner of Example 168 gives the products of the table.

    __________________________________________________________________________     Example                                                                             Starting Prostaglandin                                                                      Alcohol                                                                               Product                                               __________________________________________________________________________     169  l-13-dihydroprostaglandin-                                                                  Ethanol                                                                               l-11-deoxy-11α-(1-hydroxyethyl)-13-dihydro-          A.sub.1             prostaglandin-E.sub.1 and 11-deoxy-11α-(1-h                              ydroxy-                                                                        ethyl)-13-dihydroprostaglandin-E.sub.1 and                                     8-iso-                                                                         11-deoxy-11α-(1-hydroxyethyl)-13-dihydro-                                prostaglandin-E.sub.1                                 170  l-prostaglandin-A.sub.1                                                                     Isopropanol                                                                           l-11-deoxy-11α-(1-hydroxy-1-methylethyl)-                                prostaglandin-E.sub.1                                 171  l-prostaglandin-A.sub.3                                                                     Methanol                                                                              l-11-deoxy-11α-hydroxymethyl-prostaglandin-                              E.sub.3                                                    (EX. 109)           and l-11-deoxy-11α-hydroxymethylprostagland                              in-                                                                            E.sub.3 and 8-iso-11-deoxy-11α-hydroxymethy                              lprosta-                                                                       glandin-E.sub.3                                       172  l-15-epiprostaglandin-A.sub.2                                                               Methanol                                                                              l-11-deoxy-11α-hydroxymethyl-15-epiprosta-                               glandin-E.sub.2 and l-11-deoxy-11α-hydroxym                              ethyl-15-                                                                      epiprostaglandin E.sub.2 and 8-iso-11-deoxy-11-                                hydroxymethyl-15-epiprostaglandin-E.sub.2             173  l-15-O-acetylprosta-                                                                        Isopropanol                                                                           l-11-deoxy-11α-(1-hydroxy-1-methylethyl)-15                              -O-                                                        glandin-A.sub.2 methyl ester                                                                       acetylprostaglandin-E.sub.2 methyl ester              174  dl-prostaglandin-A.sub.2                                                                    methanol                                                                              dl-11-deoxy-11α-hydroxymethylprostaglandin-                              E.sub.2                                                                        dl-11-deoxy-11β-hydroxymethylprostaglandin-E                              .sub.2                                                                         and dl-8-iso-11α-hydroxymethylprostaglandin                              -E.sub.2                                              175  l-15-methylprostaglandin-                                                                   Methanol                                                                              l-11-deoxy-11α-hydroxymethyl-15-methylprost                              a-                                                         A.sub.2 methyl ester                                                                               glandin-E.sub.2 methyl ester; 1-11-deoxy-11β                              -hydroxy-                                                                      methyl-15-methylprostaglandin-E.sub.2 and                                      8-iso-                                                                         11-deoxy-11α-hydroxymethyl-15-methylprosta-                              glandins-E.sub.2 methyl ester                         176  l-16,16-dimethylprosta-                                                                     Methanol                                                                              l-11-deoxy-11α-(1-hydroxymethyl)-16,16-dime                              thyl-                                                      glandin-A.sub.1     prostaglandin-E.sub.1 ; l-11-deoxy-11β-(1-hy                              droxy-                                                                         methyl)-16,16-dimethylprostaglandin-E.sub.1 and                                8-iso-11-deoxy-11α-(hydroxymethyl)-16,16-di                              -                                                                              methylprostaglandin-E.sub.1                           177  l-16(R)-methylprosta-                                                                       Methanol                                                                              l-11-deoxy-11α-hydroxymethyl-16(R)-methylpr                              osta-                                                      glandin-A.sub.2     glandin-E.sub.2 ; l-11-deoxy-11β-hydroxymeth                              yl-16(R)-                                                                      methylprostaglandin-E.sub.2 and                                                8-iso-11-deoxy-11α-                                                      hydroxymethyl-16(R)-methylprostaglandin-E.sub.2       178  l-16,16-diflurorprosta-                                                                     Methanol                                                                              l-11-deoxy-11α-hydroxymethyl-16,16-difluoro                              -                                                          glandin-A.sub.2     prostaglandin-E.sub.2 ; l-11-deoxy-11β-hydro                              xymethyl-                                                                      16,16-difluoroprostaglandin-E.sub.2 and                                        8-iso-11-                                                                      deoxy-11α-hydroxymethyl-16,16-difluoroprost                              a-                                                                             glandin-E.sub.2                                       179  l-20-ethylprostaglandin-                                                                    Methanol                                                                              l-11-deoxy-11α-hydroxymethyl-20-ethyl-               A.sub.2             prostaglandin-E.sub.2 ; l-11-deoxy-11β-hydro                              xy-                                                                            methyl-20-ethylprostaglandin-E.sub.2 and 8-iso-                                11-deoxy-11α-hydroxymethyl-20-ethyl-                                     prostaglandin-E.sub.2                                 180  dl-17,20-tetranor-16-m-                                                                     Methanol                                                                              dl-11-deoxy-11α-hydroxymethyl-17,20-tetra-           trifluoromethylphenoxy-                                                                            nor-16-m-trifluoromethylphenoxyprosta-                     prostaglandin-A.sub.2                                                                              glandin-E.sub.2 ; dl-11-deoxy-11β-hydroxymet                              hyl-                                                       (Example 114)       17,20-tetranor-16-m-trifluoromethylphenoxy-                                    prostaglandin-E.sub.2 and dl-8-iso-11-deoxy-11.al                              pha.-                                                                          hydroxymethyl-17,20-tetranor-16-m-trifluoro-                                   methylprostaglandin-E.sub.2                           181  l-17,20-tetranor-16-p-                                                                      Isopropanol                                                                           l-11-deoxy-11α-(1-hydroxy-1-methylethyl)-            fluorophenoxyprosta-                                                                               17,20-tetranor-16-p-fluorophenoxyprosta-                   glandin-A.sub.2 (Example 113)                                                                      glandin-E.sub.2                                       182  l-17,20-tetranor-16-m-                                                                      Methanol                                                                              l-11-deoxy-11α-hydroxymethyl-17,20-tetranor                              -                                                          chlorophenoxyprosta-                                                                               16-m-chlorophenoxyprostaglandin-E.sub.2 ; l-11-            glandin-A.sub.2 (Example 111)                                                                      11β-hydroxymethyl-17,20-tetranor-16-m-                                    chlorophenoxyprostaglandin-E.sub.2 and l-8-iso-                                11-deoxy-11α-hydroxymethyl-17,20-tetranor-                               16-m-chlorophenoxyprostaglandin-E.sub.2               __________________________________________________________________________

EXAMPLE 183 Preparation of 11-deoxy-11β-hydroxymethyl-prostaglandin E₂

To a solution of 395 mg. (0.94 mmol) of 11-deoxy-11β-hydroxymethyl-15-O-acetyl prostaglandin E₂ methyl ester (Example 168) in 2 ml. of methanol is added 1.6 ml. of a 2.5 N aqueous sodium hydroxide solution. The solution is stirred at ambient temperature for 1.5 hour and is then diluted with 20 ml. of water, saturated with sodium chloride, acidified with 6 N aqueous hydrochloric acid and extracted twice with 50 ml. of ether. The ether solutions are combined, dried with anhydrous magnesium sulfate and concentrated in vacuo to give 320 mg. of 11-deoxy-11β-hydroxymethylprostaglandin-E₂ ; νmax 3400-2700 cm⁻¹, 1735 cm⁻¹ ; [α]_(D) ²⁵ =-59.3° (C=0.43 MeOH); CD:ΔE=-3.2.

EXAMPLE 184 Preparation of 11-deoxy-11α-hydroxymethyl-prostaglandin-E₂ and 8-iso-11-deoxy-11α-hydroxymethyl-prostaglandin-E₂

To a solution of 810 mg. of 11-deoxy-11α-hydroxymethyl-15-O-acetyl prostaglandin methyl ester (Example 168) in 5 ml. of methanol is added 2.5 ml. of 2.5 N aqueous sodium hydroxide solution. The solution is stirred at room temperature for 2.5 hours and is then diluted with 25 ml. of water, saturated with sodium chloride, acidified with 1.1 ml. 6 N aqueous hydrochloric acid and extracted twice with 20 ml. of ether. The etheral solutions are combined, dried with anhydrous magnesium sulfate and concentrated in vacuo to give 680 mg. of a mixture of 8-normal and 8-iso-11α-hydroxymethyl-15-O-acetyl prostaglandin E₂. The mixture of 8-isomers is chromatographed on a 48"×15/8" flat diamter dry column of acid washed silica gel using ethyl acetate/benzene/acetic acid (3:2:2%). The column was developed 3 times and then cored at each 0.1 Rf unit to determine the position of each isomer. Rf fractions 0.1-0.25 and 0.35-0.7 were washed with ether to give 11-deoxy-11α-hydroxymethyl prostaglandin E₂ : νmax 3400, 1720-1690, 975 cm⁻¹ ; [α]_(D) ²⁵ =-6° (c=0.21, MeOH); CD:Δε=-2.5 at 293 nm and 8-iso-11-deoxy-11α-hydroxymethyl prostaglandin-E₂ : νmax 3400, 1720-1690, 975 cm⁻¹ ; [α]_(D) ²⁵ =+37° (c=0.23, MeOH); CD:Δε=+2.04 at 293 nm, respectively.

EXAMPLE 184A Preparation of 11-deoxy-11α-(1-hydroxy-1-methylethyl)prostaglandin-E₂

The subject compound is prepared from the corresponding 15-O-acetyl methyl ester (Example 173) by saponification according to the method described in Example 183 above.

EXAMPLE 185 Preparation of 11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methyl ester and 11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methyl ester

A solution of 5.0 gm. of l-15-O-acetylprostaglandin-A₂ methyl ester and 1.2 gm. of benzophenone in 300 ml. of undistilled 1,3-dioxolan is irradiated with a medium pressure Hanovia U.V. Lamp through a Pyrex filter. After 20 minutes tlc indicates the reaction is complete. The solvent is removed in vacuo to afford 8 gm. of an oil.

The material is purified by partition chromatography using heptane-acetonitrile to give: 4.4 gm of l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetprostaglandin-E₂ methyl ester (low Rf material) and 1.72 gm of l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methyl ester (high Rf material) (tlc system 20% ethylacetate in benzene, silica gel, 2x).

The above products have nearly identical IR spectra 3400 cm⁻¹ ; 1740-1720 cm⁻¹, 975 cm⁻¹, [α]_(D) ²⁵ of high Rf material=-19° (c=0.42 MeOH), [α]_(D) ²⁵ of low Rf material=-81° (c=0.36 MeOH), CD of high Rf: 294=-3.30 CD of low Rf: -3.72.

The configuration of the 1,3-dioxolano-2-yl function is assigned to each compound on the basis of the products derived from saponification of each diester. The high Rf material, upon saponification (see Example 184) gives two products which are assigned l-11-deoxy-11α-(1,3-dioxolan-2-yl)-PGE₂ and 8-iso-11-deoxy-11α-(1,3-dioxolan-2-yl)-PGE₂. The low Rf diester upon identical saponification conditions gave only a single isomer: l-11-deoxy-11α-(1,3-dioxolan-2-yl)-PGE₂. Since it is very unlikely that a derivative with the 11α-configuration would give an 8-iso compound, the high Rf diester is assigned 11α.

EXAMPLES 186-198

Treatment of the following A type prostaglandins with the following in the manner of Example 185 is productive of the 11-(1,3-dioxolanyl-prostaglandins-E of the table.

    __________________________________________________________________________     Example                                                                             Starting Prostaglandin                                                                            Product                                                __________________________________________________________________________     186  l-13-dihydroprosta-                                                                        1,3-dioxolan                                                                          l-11-deoxy-11β-(1,3-dioxolan-2-yl)-13-                 glandin-A.sub.1    dihydroprostaglandin-E.sub.1 and 11-deoxy-                                     11α-(1,3-dioxolan-2-yl)-13-dihydro-                                      prostaglandin-E.sub.1                                  187  l-prostaglandin-A.sub.1                                                                    2-methyl-1,3-                                                                         l-11-deoxy-11α-(2-methyl-1,3-dioxolan-                            dioxolan                                                                              2-yl)-prostaglandin-E.sub.1 and l-11-deoxy-                                    11β-(2-methyl-1,3-dioxolan-2-yl)-                                         prostaglandin-E.sub.1                                  188  l-prostaglandin-A.sub.3                                                                    1,3-dioxolan                                                                          l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                   (EX. 109)          prostaglandin-E.sub.3 and l-11-deoxy-11β-                                 (1,3-dioxolan-2-yl)-prostaglandin-E.sub.3              189  l-15-epiprostaglandin-                                                                     1,3-dioxolan                                                                          l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-                A.sub.2            epi-prostaglandin-E.sub.2 and l-11-deoxy-                                      11β-(1,3-dioxolan-2-yl)-15-epi-prosta-                                    glandin-E.sub.2                                        190  dl-prostaglandin-A.sub.2                                                                   1,3-dioxolan                                                                          dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                     prostaglandin-E.sub.2 and dl-11-deoxy-11β-                                (1,3-dioxolan-2-yl)-prostaglandin-E.sub. 2             191  l-15-methylprosta-                                                                         1,3-dioxolan                                                                          l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-                glandin-A.sub.1 methyl                                                                            methylprostaglandin-E.sub.1 methyl ester                    ester              and l-11-deoxy-11β(1,3-dioxolan-2-yl)-                                    15-methylprostaglandin-E.sub.1 methyl ester            192  l-16,16-dimethylprosta-                                                                    2-methyl-1,3-                                                                         l-11-deoxy-11α-(2-methyl-1,3-dioxolan-                glandin-A.sub.2                                                                            dioxolan                                                                              2-yl)-16,16-dimethylprostaglandin-E.sub.2                                      and l-11-deoxy-11β-(2-methyl-1,3-                                         dioxolan-2-yl)-16,16-dimethylprosta-                                           glandin-E.sub.2                                        193  l-16-(R)-methylprosta-                                                                     1,3-dioxolan                                                                          l-11-deoxy-11α-(1,3-dioxolan-2-yl)-16(R)-             glandin-A.sub.2    methylprostaglandin-E.sub.2 and 1-11-deoxy-                                    11β-(1,3-dioxolan-2-yl)-16(R)-methyl-                                     prostaglandin-E.sub.2                                  194  l-16,16-difluoro-                                                                          1,3-dioxolan                                                                          l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                   prostaglandin-A.sub.2                                                                             16,16-difluoroprostaglandin-E.sub.2 and l-11-          deoxy-11β(1,3-dioxolan-2-yl)-16,16-                                       difluoroprostaglandin-E.sub.2                                                  195  l-20-ethylprosta-                                                                          1,3-dioxolan                                                                          l-11-deoxy-11α-(1,3-dioxolan-2-yl)-20-                glandin-A.sub.2                                                           ethylprostaglandin-E.sub.2 and l-11-deoxy-                                     11β-(1,3-dioxolan-2-yl)-20-ethyl-                                                                 prostaglandin-E.sub.2                                  196  dl-17,20-tetranor-                                                                         1,3-dioxolan                                                                          dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,               16-m-trifluoro-    20-tetranor-16-m-trifluoromethyl-                           phenoxyprostaglandin-                                                                             phenoxyprostaglandin-E.sub.2 and dl-11-deoxy-               A.sub.2 (Example 114)                                                     (1,3-dioxolan-2-yl)-17,20-tetranor-16-                                         m-trifluoromethylphenoxyprostaglandin-E.sub.2                                  197  l-17,20-tetranor-16-                                                                       1,3-dioxolan                                                                          l-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,                p-fluorophenoxy-   20-tetranor-16-p-fluorophenoxyprosta-                       prostaglandin-A.sub.2                                                                             glandin-E.sub.2 and l-11-deoxy-11β-(1,3-               (Example 113)      dioxolan-2-yl)-17,20-tetranor-16-p-                                            fluorophenoxyprostaglandin-E.sub.2                     198  l-17,20-tetranor-16-                                                                       1,3-dioxolan                                                                          l-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,                m-chlorophenoxy-   20-tetranor-16-m-chlorophenoxyprosta-                       prostaglandin-A.sub.2                                                                             glandin-E.sub.2 and l-11-deoxy-11β-(1,3-               (Example 111)      dioxolan-2-yl)-17,20-tetranor-16-m-                                            chloroprostaglandin-E.sub.2                            __________________________________________________________________________

EXAMPLE 199 Preparation of a mixture of the methyl esters of 11-deoxy-11α-(1-hydroxy-1-methylethyl-15-O-acetyl prostaglandin F₂ β and F₂ β and their separation

To a cold solution of 816 mg. of 11-deoxy-11α-(1-hydroxy-1-methyl ethyl)-15-O-acetylprostaglandin methyl ester (Example 173) in 10 ml. of ethanol is added to a solution of 280 mg. of sodium borohydride in 15 ml. of methanol. After 10 minutes the solution is poured into 100 ml. of saturated ammonium chloride and extracted three times with 50 ml. of ether. The ether is combined, dried with magnesium sulfate, and concentrated in vacuo to give 990 mg. of a yellow oil. The mixture of the alcohols (900 mg.) is chromatographed on a 35"×11/2" flat diameter dry column of acid washed silica using ethyl acetate/benzene (2:3). The column is cored at each 0.1 Rf unit. The following portions are removed: 0.75-1.0 and 0.2-0.5. Elution of the 0.75-1.0. portion with 20% methanol in chloroform gave 513 mg. of 11-deoxy-11α-(1-hydroxy-1-methylethyl)-15-O-acetyl prostaglandin F₂ α methyl ester as an oil; νmax 3400, 1720 cm⁻¹ ; nmr (CDCl₃ δ:4.2 (m, 1H, H-9β); [α]_(D) ²⁵ =-19°; (c=0.21, MeOH). Similar elution of the 0.2-0.5 portion gave 270 mg. of 11-deoxy-11α-(1-hydroxy-1-methylethyl-15-O-acetyl prostaglandin F₂ α/β methyl ester; νmax: 3400, 1720 cm⁻¹ pmr (CDCl3) δ:3.9 (m, 1H, H-9β) [α]_(D) ²⁵ =-26° (0.22, MeOH).

EXAMPLES 200-211

Treatment of the following E type prostaglandins with sodium borohydride in ethanol by the procedure of Example 199 provides the mixture of 9-hydroxy prostanoic acids or esters of the following table. The F.sub.α and F.sub.β components are separable by chromatography.

    __________________________________________________________________________     Example                                                                             Starting E Prostaglandin                                                                        Product F Prostaglandins                                 __________________________________________________________________________     200  l-11-deoxy-11-60 -ethylthioprosta-                                                              l-11-deoxy-11α-ethylthioprostaglandins-                 glandin-E.sub.3 (EX. 115)                                                                       F.sub.3 α and F.sub.3 β                       201  l-11-deoxy-11α-ethylthio-16-p-                                                            l-11-deoxy-11-α-ethylthio-16-p-fluorophenoxy-                            N                                                             fluorophenoxyprostaglandin-E.sub.2                                                              prostaglandins-F.sub.2 α and F.sub.2 β             (EX. 126)                                                                 202  l-11-deoxy-11α-vinyl-16(S)-methyl-                                                        l-11-deoxy-11-α-vinyl-16(S)-methylprosta-               prostaglandin-E.sub.2 (EX. 136)                                                                 glandins-F.sub.2 α and F.sub.2 β              203  l-11-deoxy-11α-methyl-13,14-di-                                                           l-11-deoxy-11α-methyl-13,14-dihydro-17,20-              hydro-17,20-tetranor-16-m-tri-                                                                  tetranor-16-m-trifluoromethylphenoxy-                         fluoromethylphenoxyprostaglandin-                                                               prostaglandins-F.sub.1 α and F.sub.1 β             E.sub.1 (EX. 145)                                                         204  l-11-deoxy-11α-methyl-16,16-di-                                                           l-11-deoxy-11α-methyl-16,16-dimethylprosta-             methyl prostaglandin-E.sub.2 (EX. 135)                                                          glandins-F.sub.2 α and F.sub.2 β              205  l-11-deoxy-11α-methyl-17,20-                                                              l-11-deoxy-11α-methyl-17,20-tetranor-16-                tetranor-16-m-chlorophenoxy-                                                                    m-chlorophenoxyprostaglandins F.sub.2 α and                              F.sub.2 β                                                prostaglandin-E.sub.2 (EX. 140)                                           206  dl-11-deoxy-11α-cyano-17,20-tetra-                                                        dl-11-deoxy-11α-cyano-17,20-tetranor-16-p-              nor-16-p-fluorophenoxyprosta-                                                                   fluorophenoxyprostaglandins-F.sub.2 α and                                F.sub.2 β                                                glandin-E.sub.2 (EX. 165)                                                 207  l-11-deoxy-11α-hydroxymethyl-                                                             1-11-deoxy-11α-hydroxymethylprostaglandin-              prostaglandin-E.sub.2 (EX. 184)                                                                 F.sub.2 β                                           208  l-11-deoxy-11α-hydroxymethyl-                                                             l-11-deoxy-11-β-hydroxymethyl-15-epiprosta-              15-epiprostaglandin-E.sub.2                                                                     glandins-F.sub.2 α and F.sub.2 β                   (EX. 172)                                                                 209  8-iso-11-deoxy-11α-hydroxy-                                                               8-iso-11-deoxy-11α-hydroxymethyl-16(R)-                 methyl-16(R)-methylprosta-                                                                      methylprostaglandins-F.sub.2 α and F.sub.2                               β                                                        glandin-E.sub.2 (EX. 177)                                                 210  1-11-deoxy-11β-(1,3-dioxolan-                                                              l-11-deoxy-11β-(1,3-dioxolan-2-yl)-prosta-               2-yl)-prostaglandin-E.sub.2 (EX. 185)                                                           glandins-F.sub.2 α and F.sub.2 β              211  l-11-deoxy-11α(1,3-dioxolan-                                                              l-11-deoxy-11α-(1,3-dioxolano-2-yl)-17,20-              2-yl)-17,20-tetranor-16-p-fluoro                                                                tetranor-16-p-fluorophenoxyprostaglandins-                    fluorophenoxyprostaglandin-                                                                     F.sub.2 α and F.sub.2 β                            E.sub.2 (EX. 197)                                                         __________________________________________________________________________

EXAMPLE 212 Separation of l-11-deoxy-11α-cyanoprostaglandin E₂ and l-11-deoxy-11α-cyanoprostaglandin-E₂ by silica gel chromatography

A solution of 2.6 gm. of a mixture of l-11-deoxy-11α-cyanoprostaglandins-E₂ and 11-deoxy-11β-cyanoprostaglandin-E₂ (Example 71) in 5 ml. of methylene chloride was placed on top of a 40"×2" flat diameter nylon column placed with acid washed silica. The column was developed with 40% ethylacetate in benzene containing 2% acetic acid. A single development required 700 ml. A total of 1700 ml. was used with 100 ml. fractions being collected. Fraction 6 contained 540 mg. of pure l-11-deoxy-11α-cyanoprostaglandin-E₂ [α]_(D) ²⁵ =0° (C=0.65 MeOH) λmax. 3400, 1730-1690; 975 cm⁻¹ ; pmr CDCl₃ (δ): 3.2-3.5 (m, 1H, H-11), 4.2-4.3 (m, 1H, H₁₅), 5.2-5.5 (m, 2H, H5, H6), 5.7-5.85 (m, 2H, H 13, H14), Δε296=-2.46. Fraction 4 consisted of primarily l-11-deoxy-11β-cyanoprostaglandin-E₂ [α]_(D) ²⁵ =35° (C=0.67 MeOH) λmax. 3400, 1730-1710, 975 cm⁻¹ ; pmr CDCl₃ (δ): 4.2 (m, 1H, H15), 5.3-5.6 (m, 2H, H5, H6), 5.6-6.0 (mM, 2H, H13, H14), Δε296=-0.26.

EXAMPLES 213-216

Treatment of the following E type prostanoic acids with lithium tri-sec-butyl borohydride in tetrahydrofuran by the method of Example 81 furnishes the 9-hydroxy prostanoic acids on the following wherein the 9-hydroxy group is cis to the 11-substituent.

    __________________________________________________________________________     Example                                                                             Starting 9-oxo prostaglandin                                                                     Product 9-hydroxy prostaglandin                         __________________________________________________________________________     213  l-11-deoxy-11β-cyanoprostaglandin-                                                          l-11-deoxy-11β-cyanoprostaglandin-F.sub.2                                 β                                                       E.sub.2 (EX. 212)                                                         214  l-11-deoxy-11α-phenylprostaglandin-                                                        l-11-deoxy-11α-phenylprostaglandin-F.sub.2                               α                                                      E.sub.2 (EX. 133)                                                         215  l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                    prostaglandin-E.sub.2 (EX. 188)                                                                  prostaglandin-F.sub.2 α                           216  dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                       dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,                17,20-tetranor-16-p-fluoro-                                                                      20-tetranor-16-p-fluoroprostaglandin-F.sub.2                                   α                                                      prostaglandin-E.sub.2 (EX. 211)                                           __________________________________________________________________________

EXAMPLE 217 Preparation of l-11-deoxy-11α-formyl-15-O-acetylprostaglandin-E₂ methyl ester from l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methyl ester

A solution of 1 gm. of l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-O-acetylprostaglandin-E₂ methyl ester (Example 185) in 20 ml. of a solution consisting of acetic acid, tetrahydrofuran and water in a 2:1:1 ratio is heated to 45° C. for 16 hours. The cooled solution is concentrated in vacuo and the residue is diluted with 100 ml. of benzene and washed twice with 100 ml. of brine. The benzene layer is separated and after drying with magnesium sulfate is concentrated in vacuo to give the subject compound: λmax: 1740-1710 cm⁻¹, 975 cm⁻¹.

EXAMPLES 218-222

Subjection of the following 11-1,3-dioxolan-2-yl prostaglandins of the table to the reaction conditions of Example 217 is productive of the products listed in the table.

    __________________________________________________________________________     Example                                                                             Starting Prostaglandin                                                                          Product Prostaglandin                                    __________________________________________________________________________     218  l-11-deoxy-11β-(2-methyl-1,3-                                                              l-11-deoxy-11β-acetylprostaglandin-E.sub.1               dioxolan-2-yl)prostaglandin-E.sub.1                                            (EX. 187)                                                                 219  l-11-deoxy-11α-(1,3-dioxolan-2-                                                           l-11-deoxy-11α-formyl-15-epi-prosta-                    yl)-15-epi-prostaglandin-E.sub.2                                                                glandin-E.sub.2                                               (EX. 189)                                                                 220  l-11-deoxy-11α-(1,3-dioxolan-2-                                                           l-11-deoxy-11α-formyl-16(R)-methylprosta-               yl)-16(R)-methylprostaglandin-                                                                  glandin-E.sub.2                                               E.sub.2 (EX. 193)                                                         221  l-11-deoxy-11β-(1,3-dioxolan-2-                                                            l-11-deoxy-11β-formyl-16,16-difluoroprosta-              yl)-16,16-difluoroprosta-                                                                       glandin-E.sub.2                                               glandin-E.sub.2 (EX. 194)                                                 221A dl-11-deoxy-11α-(1,3-dioxolan-2-                                                          dl-11-deoxy-11α-formyl-17,20-tetranor-16-               yl)-17,20-tetranor-16-m-tri-                                                                    m-trifluoromethylprostaglandin-E.sub.2                        fluoromethylprostaglandin-E.sub.2                                              (EX. 196)                                                                 222  l-11-deoxy-11α-(1,3-dioxolan-2-                                                           l-11-deoxy-11α-formyl-17,20-tetranor-16-                yl)-17,20-tetranor-16-m-chloro-                                                                 m-chlorophenoxyprostaglandin-E.sub.2                          phenoxyprostaglandin-E.sub.2 (EX. 198)                                    222A l-11-deoxy-11β-(1,3-dioxolan-2-                                                            l-11-deoxy-11β-formylprostaglandin E.sub.2               yl)prostaglandin E.sub.2 (EX. 210)                                        222B l-11-deoxy-11β-(1,3-dioxolo-2-                                                             l-11-deoxy-11β-formylprostaglandin-F.sub.2               yl)prostaglandin F.sub.2 (EX. 210)                                        222C l-11-deoxy-11β-(1,3-dioxolan-2-                                                            l-11-deoxy-11β-formylprostaglandin-E.sub.2               yl)prostaglandin E.sub.2 (EX. 185)                                        __________________________________________________________________________

EXAMPLES 223-235

Treatment of the following A type prostaglandins with the indicated lower alkanoylthiol carboxylic acid in the manner of Example 13 is productive of the 11-lower alkanoylthioprostaglandins of the table.

    __________________________________________________________________________                        Reagent thiol                                                                          Product 11α/β-11-deoxy-alkanylthio-                                 N                                                   Example                                                                             Starting Prostaglandin A                                                                     alkanoic acid                                                                          prostaglandin E                                     __________________________________________________________________________     223  l-13-dihydroprostaglandin-A.sub.1                                                            thiolpropnaoic                                                                         l-11-deoxy-11α-propanoylthio-13-                                 acid    dihydroprostaglandin-E.sub.1 and 11-                                           deoxy-11β-propanoylthiol-13-dihydro-                                      prostaglandin-E.sub.1                               224  l-prostaglandin-A.sub.3                                                                      thiolacetic                                                                            l-11-deoxy-11α-acetylthioprosta-                                 acid    glandin-E.sub.3 and l-11-deoxy-11β-acetyl-                                O                                                                              thioprostaglandin-E.sub.3                           225  l-prostaglandin-A.sub.2                                                                      thiolacetic                                                                            l-11-deoxy-11α-acetylthioprosta-                   methyl ester  acid    glandin-E.sub.2 methyl ester and l-11-deoxy-                                   11β-acetylthioprostaglandin-E.sub.2                                       methyl ester                                        226  l-15-epiprostaglandin-A.sub.2                                                                thiolacetic                                                                            l-11-deoxy-11α-acetylthio-15-epi-pro-                            acid    staglandin-E.sub.2 and l-11-deoxy-11β-                                    acetylthio-15-epiprostaglandin-E.sub.2              227  dl-prostaglandin-A.sub.1                                                                     thiolacetic                                                                            dl-11-deoxy-11α-acetylthioprosta-                                acid    glandin-E.sub.1 and dl-11-deoxy-11β-acetyl                                -                                                                              thiolprostaglandin-E.sub.1                          228  l-16,16-dimethylprosta-                                                                      thiolacetic                                                                            l-11-deoxy-11α-acetylthio-16,16-di-                glandin-A.sub.1                                                                              acid    methylprostaglandin-E.sub.1 and l-11-deoxy-                                    11β-acetylthio-16,16-dimethylprosta-                                      glandin-E.sub.1                                     229  l-16,16-dimethylprosta-                                                                      thiolacetic                                                                            l-11-deoxy-11α-acetylthiol-16,16-di-               glandin-A.sub.2                                                                              acid    methylprostaglandin-E.sub.2 and l-11-deoxy-                                    11β-acetylthio-16,16-dimethylprosta-                                      glandin-E.sub.2                                     230  l-16(S)-methylprosta-                                                                        thiolacetic                                                                            l-11-deoxy-11α-acetylthiol-16(S)-                  glandin-A.sub.2                                                                              acid    methylprostaglandin-E.sub.2 and l-11-                                          deoxy-11β-acetylthio-16(S)-methyl-                                        prostaglandin-E.sub.2                               231  l-16-fluoroprostaglandin-                                                                    thiolacetic                                                                            l-11-deoxy-11α-acetylthio-16-fluoro-               A.sub.2       acid    prostaglandin-E.sub.2 and l-11-deoxy-11β-                                 acetylthio-16-fluoroprostaglandin-E.sub.2           232  l-20-methylprostaglandin-                                                                    thiolacetic                                                                            l-11-deoxy-11α-acetylthio-20-methyl-               A.sub.2       acid    prostaglandin-E.sub.2 and l-11-deoxy-11β-                                 acetylthiol-20-methylprostaglandin-                                            E.sub.2                                             233  dl-17,20-tetranor-16-m-                                                                      thiolacetic                                                                            dl-11-deoxy-11α-acetylthio-17,20-                  trifluoromethylphenoxy-                                                                      acid    tetranor-16-m-trifluoromethylphenoxy-                    prostaglandin-E.sub.2 prostaglandin-E.sub.2 and dl-11-                         (EX. 114)             deoxy-11β-acetylthiol-17,20-tetranor-                                     16-m-trifluoromethylphenoxyprostaglan-                                         in-E.sub.2                                          234  l-17,20-tetranor-16-p-                                                                       thiolacetic                                                                            l-11-deoxy-11α-acetylthio-17,20-                   fluorophenoxyprosta-                                                                         acid    tetranor-16-p-fluorophenoxyprosta-                       glandin-A.sub.2       glandin-E.sub.2 and l-11-deoxy-11β-acetyl-                                N                                                        (EX. 113)             thiol-17,20-tetranor-16-p-fluoro-                                              phenoxyprostaglandin-E.sub.2                        235  l-17,20-tetranor-16-m-                                                                       thiolacetic                                                                            l-11-deoxy-11α-acetylthio-17,20-                   chlorophenoxyprosta-                                                                         acid    tetranor-16-m-chlorophenoxyprosta-                       glandin-A.sub.2       glandin-E.sub.2 and l-11-deoxy-11β-acetyl-                                O                                                        (EX. 111)             thiol-17,20-tetranor-16-m-chloro-                                              phenoxyprostaglandin-E.sub.2                        __________________________________________________________________________

EXAMPLE 236 Preparation of l-11-deoxy-11α-mercaptoprostaglandin-F₂ α

A solution of 2.25 gm. of the crude prostaglandin A₂ extract (60% real) from plexaura homomalla in 10 ml. of thiolacetic acid is heated at 60° C. for 3 hours. After cooling, the solution is diluted with 20 ml. of benzene and concentrated in vacuo to an oil. Benzene (40 ml.) is added and removed in vacuo to provide 2.6 gm. of an oil.

The crude oil is purified by partition chromatography using heptane methanol on celite to provide 1.4 gm. of l-11α/β-acetylthio-11-deoxyprostaglandin-E₂ as an oil; λmax: 1740, 1720, 975 cm⁻¹.

To a -78° C. solution of 15 ml. of 1.0 M lithium tri-sec-butylborohydride in tetrahydrofuran/pentane (1:1) is added 1.15 gm. (2.8 mmol) of l-11α/β-acetylthio-11-deoxyprostaglandin-E₂ in 5 ml. of tetrahydrofuran. After 30 minutes at -78° C., 10 ml. of water is added and the resulting mixture is stirred in a 30° C. bath for 30 minutes. The solution is diluted with an additional 30 ml. of water and extracted four times with 50 ml. of ether.

The aqueous solution is acidified to pH 4 with 2.5 ml of 6 N hydrochloric acid, saturated with sodium chloride and extracted twice with 50 ml. of ether and twice with 50 ml. of ethyl acetate. The combined organic extracts are dried with magnesium sulfate and concentration in vacuo to provide 900 mg. of an oil.

The crude oil is purified on Wolem acid-washed silica-gel using chloroform as solvent to provide 240 mg. of l-11-deoxy-11α-mercaptoprostaglandin-F₂ α as a was: λmax: 3400, 1700, 975 cm⁻¹ ; pmr (CDCl₃): δ(4.1-4.4, m, 2-H, H9_(b) and H₁₅), (5.05-5.25, M, 4H, exchangeable with CD₃ OD), (5.25-5.7, M, 4H, H₅, H₆, H₁₃ and H₁₄); [α]_(D) ²⁵ =+16° (C=0.35 MeOH).

EXAMPLE 237 Preparation of 11α-cyano-11-deoxyprostaglandin F₂ α,11β-cyano-11-deoxyprostaglandin F₂ β and 11β-cyano-11-deoxypropstaglandin F₂ α

To a solution of 2.84 g. of 40 in 15 ml. of tetrahydrofuran at -78° C. is added 14 ml. of a 0.65 M solution of LPBH. After 60 minutes at -78° C. tlc indicated some ketone remaining after warming to room temperature, the solvent is removed in vacuo and 10 ml. of methanol, 5 ml. of water and 5 ml. of 2.5 N sodium hydroxide are added. After 3 hours, 50 ml. of water is added and the solution is extracted with 3×50 ml. of ether. The aqueous phase is acidified with 6 N hydrochloric acid, saturated with sodium chloride and extracted with ether. The ether is washed with brine, dried and evaporated to yield 2.4 g. of an oil that consists of 4 spots of tlc (EtOAc-benzene-HOAc: 40:60:1.5, 2×, silica-gel).

The oil is chromatographed on a 30"×11/2" flat diameter silica-gel) dry column using EtOAc-benzene-HOAc (60-40:3) as solvent. TLC of plugs indicates pooling the following Rf fractions: 0.45-0.65 (A), 0.65-0.73 (B) and 0.73-0.83 (C). The compound is eluted from the silica-gel with 20% MeOH/CHCl₃ to give: A: 912 mg., B: 650 mg., and C: 550 mg.

A and B are combined and rechromatographed on a 30"×11/2" flat diameter dry silica-gel column using ETOAc-OH-HOAc (40-60:3). TLC indicates combining Fr: 0.2-0.41 (A), 0.41-0.48 (B) and 0.48-0.7 (C). Elution from the absorbant will give: A': 230 mg., B': 210 mg. and C': 650 mg. TLC indicates A' nearly pure. Recrystallization of A' from ETOAc-hexane gives 130 mg. of 11β-cyano-11-deoxyprostaglandin-F₂ β: m.p. 76°-78° C.; λmax. 3400-2700, 2220, 1710 cm⁻¹ ; pmr (CDCl₃): δ2.98 (q, 1H, W_(1/2) =20H_(z), H₁₁ α), 3.96 (q, 1H, W_(1/2) =20H_(z), H₁₁ α), 3.96 (q, 1H, W_(1/2) =20H_(z), H₉ α), 4.17 (q, 1H, W_(1/2) =18H_(z), H₁₅), 5.48 (m, 2H, H₅,6), 5.70 (m, 2H, H₁₃,14); [α]_(D) ²⁵ =+68.8° (C+0.93 chloroform). N.O.E.²⁰ indicates that H-11 and the beta alkyl chain are trans.

A portion of the major component (C+C' combined, 790 mg.) is treated with a semicarbizide-acetic acid solution to form the semicarbizone of unreacted ketone that possesses nearly the same Rf as the products. The resulting oil is chromatographed on a 24"×1" flat diameter dry silica-gel column using EtOAc-benzene-HOAc (20:30:1). Elution of the material from Rf 0.35-0.55 with 20% methanol-chloroform give 375 mg. of 11α-cyano-11-deoxyprostaglandin F₂ α as an oil that solidifies upon storage at -10°; λmax 3400-2200, 2220, 1710 cm⁻¹ ; pmr (CDCl₃): δ2.6 (m, ˜2H, H₁₁,12), 4.17-4.3 (m, 2H, H₉β,15), 5.50 (m, 3H, H₅,6,13), 5.76 (d-d, 1H, J=15 Hz, Jobs 14,15=5 Hz, H₁₄); [α]_(D) ²⁵ =+2.24°, (C=0.713, chloroform). N.O.E.²⁰ indicates that H-11 and the beta alkyl chain were cis.

B' is recrystallized to give a solid that is a mixture of 11β-cyano-11-deoxyprostaglandin F₂ β and the next less plar component. The pmr spectrum (CDCl₃) indicated this material consistes of 11β-cyano-11-deoxyprostaglandin F₂β and 11β-cyano-11-deoxyprostaglandin F₂β and (1:1): δ2.96 (two overlapping quartets, H₁₁α), 3.97 (q, 1/2H, W 1/2-20H_(z), H₉α), 4.18 (m, H₁₅ and H₉β, 11/2H), 5.48 (m, H₅,6) and 5.65-5.9 (m, H₁₃,14). Compounds are assumed epimeric at C-9 since their H₁₁ resonances are nearly coincident.

EXAMPLES 238-326

Carbonyl reduction of the listed prostaglandin E derivatives by the procedure of the example designated will furnish the product prostaglandins F of the following table. In these instances where a prostaglandin Fα and a prostaglandin F.sub.β are formed, these components are separable by chromatographic procedures (see Example 237 for an illustrative example).

    __________________________________________________________________________     Ex- Starting 11-Substituted                                                                         Method                                                                               Product 11-Substituted                              ample                                                                              Prostaglandin-E  of Example                                                                           Prostaglandin F                                     __________________________________________________________________________     238 11-deoxyprostaglandin methyl                                                                    81    11-deoxyprostaglandin F.sub.2α                    ester (Ex. 46)                                                             239 11-deoxy-11α-vinylprosta-                                                                 81    11-deoxy-11α-vinylprostaglandin                                          F.sub.2α                                          glandin E.sub.2 methyl ester                                                   (Ex. 28a)                                                                  240 11-deoxy-11α-hydroxymethyl-                                                               80    11-deoxy-11α-hydroxymethylprosta-                 prostaglandin-E.sub.2 (Ex. 83)                                                                        glandin-F.sub.2α                              241 11-deoxy-11α-hydroxymethyl-                                                               80    11-deoxy-11α-hydroxymethylprosta-                 prostaglandin-E.sub.2 (Ex. 184)                                                                       glandin-F.sub.2α                              242 11α-acetylthio-11-deoxy-                                                                  80    11α-acetylthio-11-deoxyprosta-                    prostaglandin-E.sub.2 (Ex. 14)                                                                        glandin-F.sub.2α                              243 11-deoxy-11α-ethylprosta-                                                                 81    11-deoxy-11α-ethylprostaglandin-F.sub.2.a                                lpha.                                                   glandin-E.sub.2 methyl ester                                                   (Ex. 20)                                                                   244 11-deoxy-11,15-bisdeoxy-11,                                                                     81    11,15-bisdeoxy-11,15-dimethylprosta-                    15-dimethylprostaglandin-                                                                             glandin-F.sub.2α                                  E.sub.2 (Ex. 17)                                                           245 11-deoxy-11α-(1-hydroxy-                                                                  80    11-deoxy-11α-(1-hydroxy-1-methyl-                 1-methylethyl)prosta-  ethyl)prostaglandin-F.sub.2α                      glandin-E.sub.2 (Ex. 184A)                                                 __________________________________________________________________________     Ex- Starting 11α-alkylthio-11-                                                                Method                                                                               Product                                             ample                                                                              deoxyprostaglandin E                                                                            of Example                                                                           11α-alkylthio-11-deoxyprostaglandin           __________________________________________________________________________                                F                                                   246 l-11-deoxy-11α-ethylthio-                                                                 80    l-11-deoxy-11α-ethylthioprostaglandin-F.s                                ub.3α                                             prostaglandin-E.sub.3 (Ex. 115)                                            247 l-11-deoxy-11α-methylthio-                                                                80    l-11-deoxy-11α-methylthio-15-epi-prosta-          15-epi-prostaglandin-E.sub.2                                                                          glandin-F.sub.2α                                  (Ex. 116)                                                                  248 l-11-deoxy-11α-(1-propyl-                                                                 81    l-11-deoxy-11α-(propylthio)-15-epi-O-acet                                yl-                                                     thio)-15-epi-O-acetyl- prostaglandin-F.sub.2α  methyl ester              prostaglandin-E.sub.2 methyl                                                   ester (Ex. 117)                                                            249 dl-11-deoxy-11α-butylthio-                                                                80    dl-11-deoxy-11α-butylthioprostaglandin-F.                                sub.1α                                            prostaglandin-E.sub.1 (Ex. 118)                                            250 l-11-deoxy-11α-methylthio-                                                                81    l-11-deoxy-11α-methylthioprostaglandin-F.                                sub.1α                                            prostaglandin-E.sub.1 methyl                                                                          methyl ester                                            ester (Ex. 119)                                                            251 l-11-deoxy-11α-ethylthio-15-                                                              81    l-11-deoxy-11α-ethylthio-15-methylprostag                                landin-                                                 methylprostaglandin-E.sub.2                                                                           F.sub.2α methyl ester                             methyl ester (Ex. 120)                                                     252 l-11-deoxy-11α-propylthiol-                                                               80    l-11-deoxy-11α-propylthiol-16,16-dimethyl                                -                                                       16,16-dimethylprosta-  prostaglandin-F.sub.2α                            glandin-E.sub.2 (Ex. 121)                                                  253 l-11-deoxy-11α-ethylthio-                                                                 80    l-11-deoxy-11α-ethylthio-16(S)-methylpros                                ta-                                                     16(S)-methylprostaglandin-                                                                            glandin-F.sub.2α                                  E.sub.2 (Ex. 122)                                                          254 l-11-deoxy-11α-methylthio-                                                                80    l-11-deoxy-11α-methylthio-16,16-difluoro-                                T                                                       16,16-difluoroprostaglandin-                                                                          prostaglandin-F.sub.2α                            E.sub.2 (Ex. 123)                                                          255 l-11-deoxy-11α-methylthio-                                                                80    l-11-deoxy-11α-methylthio-16-fluoroprosta                                -                                                       16-fluoroprostaglandin-                                                                               glandin-F.sub.2α                                  E.sub.2 (Ex. 124)                                                          256 l-11-deoxy-11α-methylthiol-                                                               80    l-11-deoxy-11α-methylthiol-20-ethylprosta                                -                                                       20-ethylprostaglandin-E.sub.2                                                                         glandin-F.sub.2α                                  (Ex. 125)                                                                  257 dl-11-deoxy-11α-ethylthio-                                                                80    dl-11-deoxy-11α-ethylthio-17,20-tetranor-                                16-                                                     17,20-tetranor-16-p-   p-fluorophenoxyprostaglandin-F.sub.2α             fluorophenoxyprostaglandin-                                                    E.sub.2 (Ex. 126)                                                          258 dl-11-deoxy-11α-methylthio-                                                               80    dl-11-deoxy-11α-methylthio-17,20-tetranor                                -16-                                                    17,20-tetranor-16-m-tri-                                                                              m-trifluoromethylphenoxyprostaglandin-F.sub.2.a                                lpha.                                                   fluoromethylphenoxyprosta-                                                     glandin-E.sub.2 (Ex. 127)                                                  259 l-11-deoxy-11α-butylthio-                                                                 80    l-11-deoxy-11α-butylthio-17,20-tetranor-1                                6-m-                                                    17,20-tetranor-16-m-tri-                                                                              trifluoromethylphenoxyprostaglandin-F.sub.2.alp                                ha.                                                     fluoromethylphenoxyprosta-                                                     glandin-E.sub.2 (Ex. 128)                                                  260 l-11-deoxy-11α-methylthio-                                                                80    l-11-deoxy-11α-methylthio-17,20-tetranor-                                16-m-                                                   17,20-tetranor-16-m-chloro-                                                                           chlorophenoxyprostaglandin-F.sub.2α               phenoxyprostaglandin-E.sub.2                                                   (Ex. 129)                                                                  __________________________________________________________________________     Ex- Starting 11-Substituted-11-                                                                     Method                                                                               Product                                             ample                                                                              deoxyprostaglandin E                                                                            of Example                                                                           11-Substituted-11-deoxyprostaglandin                __________________________________________________________________________                                F                                                   261 l-11-deoxy-11α-methylprosta-                                                              80    l-11-deoxy-11α-methylprostaglandin-F.sub.                                3α                                                glandin-E.sub.3 (Ex. 130)                                                  262 l-11-deoxy-11α-methylprosta-                                                              81    l-11-deoxy-11α-methylprostaglandin-F.sub.                                2α                                                glandin-E.sub.2 methyl ester                                                                          methyl ester                                            (Ex. 131)                                                                  263 l-11-deoxy-11α-ethyl-15-epi-                                                              80    l-11-deoxy-11α-ethyl-15-epi-prostaglandin                                -                                                       prostaglandin-E.sub.2 (Ex. 132)                                                                       F.sub.2α                                      264 dl-11-deoxy-11α-phenylprosta-                                                             81    dl-11-deoxy-11α-phenylprostaglandin-E.sub                                .2α  and                                          glandin E.sub.2 and dl-11-deoxy-                                                                      dl-11-deoxy-11α-phenylprostaglandin-F.sub                                .2α  methyl                                       11-phenylprostaglandin-E.sub.2                                                                        ester                                                   methyl ester (Ex. 133)                                                     265 l-deoxy-11α-methyl-15-methyl-                                                             81    l-deoxy-11α-methyl-15-methylprostaglandin                                -                                                       prostaglandin-E.sub.2 methyl                                                                          F.sub.2α methyl ester                             ester (Ex. 134)                                                            266 l-11-deoxy-11α-methyl-16,16-                                                              81    l-11-deoxy-11α-methyl-16,16-dimethylprost                                a-                                                      dimethylprostaglandin-E.sub.1                                                                         glandin-F.sub.1α methyl ester                     methyl ester (Ex. 135)                                                     267 l-11-deoxy-11α-vinyl-16(S)-                                                               80    l-11-deoxy-11α-vinyl-16(S)-methylprosta-                                 0                                                       methylprostaglandin-E.sub.2                                                                           glandin-F.sub.2α                                  (Ex. 136)                                                                  268 l-11-deoxy-11α-(1-butenyl)-                                                               80    l-11-deoxy-11α-(1-butenyl)-16-fluoroprost                                a-                                                      16-fluoroprostaglandin-E.sub. 2                                                                       glandin-F.sub.2α                                  (Ex. 137)                                                                  269 l-11-deoxy-11α-propenyl-20-                                                               80    l-11-deoxy-11α-propenyl-20-ethylprostagla                                ndin-                                                   ethylprostaglandin-E.sub.2                                                                            F.sub.2α                                          (Ex. 138)                                                                  270 l-11-deoxy-11α-methyl-17,-                                                                80    l-11-deoxy-11α-methyl-17,20-tetranor-16-m                                -tri-                                                   20-tetranor-16-m-trifluoro-                                                                           fluoromethylphenylprostaglandin-F.sub.2α          methylphenylprostaglandin-                                                     E.sub.2 (Ex. 139)                                                          271 l-11-deoxy-11α-methyl-17,-                                                                80    l-11-deoxy-11α-methyl-17,20-tetranor-16-m                                -                                                       20-tetranor-16-m-chloro-                                                                              chlorophenoxyprostaglandin-F.sub.2α               phenoxyprostaglandin-E.sub.2                                                   (Ex. 140)                                                                    271A                                                                             l-11-deoxy-11α-vinyl-17,-                                                                 80    l-11-deoxy-11α-vinyl-17,20-tetranor-16-m-                                tri-                                                    20-tetranor-16-m-trifluoro-                                                                           fluoromethylphenoxyprostaglandin-F.sub.2α         methylphenoxyprostaglandin-                                                    E.sub.2 (Ex. 140A)                                                           271B                                                                             l-11-deoxy-11α-vinyl-17,-                                                                 80    l-11-deoxy-11α-vinyl-17,20-tetranor-16-m-         20-tetranor-16-m-chloro-                                                                              chlorophenoxyprostaglandin-F.sub.2α               phenoxyprostaglandin-E.sub.2                                                   (Ex. 140B)                                                                   271C                                                                             l-11-deoxy-11α-vinyl-17,20-                                                               80    l-11-deoxy-11α-vinyl-17,20-tetranor-16-p-                                fluoro-                                                 tetranor-16-p-fluorophen-                                                                             phenoxyprostaglandin-F.sub.2α                     oxyprostaglandin-E.sub.2                                                       (Ex. 140C)                                                                  271D                                                                              l-11-deoxy-11α-vinyl-16,16-                                                               80    l-11-deoxy-11α-vinyl-16,16-dimethylprosta                                -                                                       dimethylprostaglandin-E.sub.2                                                                         glandin-F.sub.2α                                  (Ex. 140D)                                                                 __________________________________________________________________________     Ex- Starting 13,14-dihydro-                                                                         Method                                                    ample                                                                              prostaglandin E.sub.1                                                                           of Example                                                                           Product 13,14-dihydroprostaglandin                                             F.sub.1α                                      __________________________________________________________________________     272 l-11-deoxy-11α-methyl-13,14-                                                              81    l-11-deoxy-11α-methyl-13,14-dihydro-15-me                                thyl-                                                   dihydro-15-methyl-prosta-                                                                             prostaglandin-F.sub.1α methyl ester           273 l-11-deoxy-11α-ethyl-15-epi-                                                              80    l-11-deoxy-11α-ethyl-15-epi-13,14-dihydro                                prosta-                                                 13,14-dihydroprostaglandin-                                                                           glandin-F.sub.1α                                  E.sub.1 (Ex. 142)                                                          274 l-11-deoxy-11α-methyl-13,14-                                                              81    l-11-deoxy-11α-methyl-13,14-dihydro-16,16                                -di-                                                    dihydro-16,16-dimethyl-                                                                               methylprostaglandin-F.sub.1α methyl                                      ester                                                   prostaglandin-E.sub.1 methyl                                                   ester (Ex. 143)                                                            275 l-11-deoxy-11α-phenyl-13,14-di-                                                           81    l-11-deoxy-11α-phenyl-13,14-dihydroprosta                                -                                                       hydroprostaglandin-E.sub.1 methyl                                                                     glandin-F.sub.1α methyl ester                     ester (Ex. 144)                                                            276 l-11-deoxy-11α-methyl-13,14-                                                              80    l-11-deoxy-11α-methyl-13,14-dihydro-17,20                                -tetra-                                                 dihydro-17,20-tetranor-16-                                                                            nor-16-m-trifluoromethylphenoxyprostaglandin-           m-trifluoromethylphenoxy-                                                                             F.sub.1α                                          prostaglandin-E.sub.1                                                      __________________________________________________________________________     Ex- 11α/β-cyano-11-deoxy-                                                                Method                                                    ample                                                                              prostaglandin E  of Example                                                                           Product 11α/β-cyano-11-deoxyprostagl                                andin F                                             __________________________________________________________________________     277 l-11-deoxy-11α-cyanoprosta-                                                               80    l-11-deoxy-11α-cyanoprostaglandin-F.sub.3                                α and                                             glandin-E.sub.3 and l-11-deoxy-                                                                       l-11-deoxy-11β-cyanoprostaglandin-F.sub.3.                                beta.                                                   11β-cyanoprostaglandin-E.sub.3                                            (Ex. 158)                                                                  278 dl-11-deoxy-11α-cyanoprosta-                                                              80    dl-11-deoxy-11α-cyanoprostaglandin-F.sub.                                2α and                                            glandin-E.sub.2 and dl-11-deoxy-                                                                      dl-11-deoxy-11β-cyanoprostaglandin-F.sub.2                                β                                                  11β-cyanoprostaglandin-E.sub.2                                            (Ex. 159)                                                                  279 l-11-deoxy-11α-cyano-15-                                                                  81    l-11-deoxy-11α-cyano-15-methylprostagland                                in-F.sub.2α                                       methylprostaglandin-E.sub.2                                                                           and l-11-deoxy-11β-cyano-15-methylprosta-          and l-11-deoxy-11β-cyano-                                                                        glandin-F.sub.2β methyl esters                     15-methylprostaglandin-                                                        E.sub.2 methyl esters (Ex. 160)                                            280 l-11-deoxy-11α-cyano-16,16-                                                               80    l-11-deoxy-11α-cyano-16,16-dimethylprosta                                -                                                       dimethylprostaglandin-E.sub.2                                                                         glandin-F.sub.2β and l-11-deoxy-11β-c                                yano-16,16-                                             and l-11-deoxy-11β-cyano-                                                                        dimethylprostaglandin-F.sub.2α                    16,16-dimethylprosta-                                                          glandin-E.sub.2 (Ex. 161)                                                  281 l-11-deoxy-11α-cyano-16(S)-                                                               80    l-11-deoxy-11α-cyano-16(S)-methylprostagl                                andin-                                                  methylprostaglandin-E.sub.2                                                                           F.sub.2α and l-11-deoxy-11β-cyano-16                                (S)-methyl                                              and l-11-deoxy-11β-cyano-                                                                        prostaglandin-F.sub.2β                             16(S)-methylprostaglandin-                                                     E.sub.2 (Ex. 162)                                                          __________________________________________________________________________     Ex- Starting 11α/β-cyano-11-                                                             Method                                                    ample                                                                              deoxyprostaglandin-E                                                                            of Example                                                                           Product 11α/β-cyano-11-deoxyprostagl                                andin F                                             __________________________________________________________________________     282 l-11-deoxy-11α-cyano-16,16-                                                               80    l-11-deoxy-11α-cyano-16,16-difluoroprosta                                -                                                       difluoroprostaglandin-E.sub.2                                                                         glandin-F.sub.2α and l-11-deoxy-11β-                                cyano-16,16-di-                                         and l-11-deoxy-11β-cyano-16,                                                                     fluoroprostaglandin-F.sub.2α                      16-difluoroprostaglandin-                                                      E.sub.2 (Ex. 163)                                                          283 l-11-deoxy-11α-cyano-16-                                                                  80    l-11-deoxy-11α-cyano-16-fluoroprostagland                                in-F.sub.2α                                       fluoroprostaglandin-E.sub.2                                                                           and d-11-deoxy-11β-cyano-16-fluoroprosta-          and d-11-deoxy-11β-cyano-                                                                        glandin-F.sub.2α                                  16-fluoroprostaglandin-                                                        E.sub.2 (Ex. 164)                                                          284 dl-11-deoxy-11α-cyano-17,20-                                                              80    dl-11-deoxy-11α-cyano-17,20-tetranor-16-p                                -                                                       tetranor-16-p-fluorophen-                                                                             fluorophenoxyprostaglandin-F.sub.2α and                                  dl-11-deoxy-                                            oxyprostaglandin-E.sub.2 and dl-                                                                      11β-cyano-17,20-tetranor-16-p-fluorophenox                                y-                                                      11-deoxy-11β-cyano-17,20-                                                                        prostaglandin-F.sub.2α                            tetranor-16-p-fluorophen-                                                      oxyprostaglandin-E.sub.2 (Ex. 165)                                         285 l-11-deoxy-11α-cyano-17,20-                                                               80    l-11-deoxy-11α-cyano-17,20-tetranor-16-m-                                tri-                                                    tetranor-16-m-trifluoro-                                                                              fluoromethylphenoxyprostaglandin-F.sub.2α                                 and l-11-                                              methylphenoxyprostaglandin-                                                                           deoxy-11β-cyano-17,20-tetranor-16-m-triflu                                oro-                                                    E.sub.2 and l-11-deoxy-11β-                                                                      methylphenoxyprostaglandin-F.sub.2α               cyano-17,20-tetranor-16-                                                       m-trifluoromethylphenoxy-                                                      prostaglandin-E.sub.2 (Ex. 166)                                            286 l-11-deoxy-11α-cyano-17,20-                                                               80    l-11-deoxy-11α-cyano-17,20-tetranor-16-m-                                chloro-                                                 tetranor-16-m-chlorophenoxy-                                                                          phenoxyprostaglandin-F.sub.2α and                                        l-11-deoxy-11-                                          prostaglandin-E.sub.2 and l-11-                                                                       cyano-17,20-tetranor-16-m-chlorophenoxyprosta-          deoxy-11β-cyano-17,20-tetra-                                                                     glandin-F.sub.2β                                   nor-16-m-chlorophenoxyprosta-                                                  glandin-E.sub.2 (Ex. 167)                                                  __________________________________________________________________________     Ex- Starting 11-Substituted-11-                                                                     Method                                                                               Product                                             ample                                                                              deoxy-prostaglandin E                                                                           of Example                                                                           11-Substituted-11-deoxyprostaglandin                __________________________________________________________________________                                F                                                   287 dl-11-deoxy-11α-hydroxyprosta-                                                            80    dl-11-deoxy-11α-hydroxymethylprostaglandi                                n-F.sub.2α                                        glandin-E.sub.2 ; dl-11-deoxy-11β-                                                               dl-11-deoxy-11β-hydroxymethylprostaglandin                                -F.sub.2α                                         hydroxymethylprostaglandin-E.sub.2                                                                    and dl-8-iso-11α-hydroxymethylprostagland                                in-F.sub.2α                                       (Ex. 174)                                                                  288 l-11-deoxy-11α-hydroxymethyl-15-                                                          81    l-11-deoxy-11α-hydroxymethyl-15-methylpro                                sta-                                                    methylprostaglandin-E.sub.2 methyl                                                                    glandin-F.sub.2α methyl ester;                                           l-11-deoxy-11β-                                    ester; l-11-deoxy-11β-hydroxy-                                                                   hydroxymethyl-15-methylprostaglandin-F.sub.2.al                                pha. and                                                methyl-15-methylprostaglandin-                                                                        8-iso-11-deoxy-11α-hydroxymethyl-15-methy                                l-                                                      E.sub.2 and 8-iso-11-deoxy-11α-                                                                 prostaglandins-F.sub.2α  methyl ester             hydroxymethyl-15-methylprosta-                                                 glandins-E.sub.2  methyl ester                                                 (Ex. 175)                                                                  289 l-11-deoxy-11α-(1-hydroxy-                                                                80    l-11-deoxy-11α-(1-hydroxymethyl)-16,16-di                                methyl-                                                 methyl)-16,16-dimethylprosta-                                                                         prostaglandin-F.sub.1α ; l-11-deoxy                                      11α-(1-hydroxy-                                   glandin-E.sub.1 ; l-11-deoxy-11β-                                                                methyl)-16,16-dimethylprostaglandin-F.sub.1.alp                                ha. and                                                 (1-hydroxymethyl)-16,16-di-                                                                           8-iso-11-deoxy-11α-(hydroxymethyl)-16,16-                                di-                                                     methylprostaglandin-E.sub.1 and                                                                       methylprostaglandin-F.sub.1α                      8-iso-11-deoxy-11α-(hydroxy-                                             methyl)-16,16-dimethylprosta-                                                  glandin-E.sub.1 (Ex. 176)                                                  290 l-11-deoxy-11α-hydroxy-                                                                   80    l-11-deoxy-11α-hydroxymethyl-16(R)-methyl                                prosta-                                                 methyl-16(R)-methylprosta-                                                                            glandin-F.sub.  2 ; l-11-deoxy-11β-hydroxy                                methyl-16(R)-                                           glandin-E.sub.2 ; l-11-deoxy-11β-                                                                methylprostaglandin-F.sub.2α and                                         8-iso-11-deoxy-                                         hydroxymethyl-16(R)-   11α-hydroxymethyl-16(R)-methylprostagland                                in-                                                     methylprostaglandin-E.sub.2                                                                           F.sub.2α                                          and dl-8-iso-11α-hydroxymethyl-                                          prostaglandin-E.sub.2  (Ex. 177)                                           291 l-11-deoxy-11α-hydroxy-                                                                   80    l-11-deoxy-11α-hydroxymethyl-16,16-difluo                                ro-                                                     methyl-16,16-difluoro- prostaglandin-F.sub.2α ;                                                 l-11-deoxy-11β-hydroxy-                            prostaglandin-E.sub.2 ; l-11-                                                                         methyl-16,16-difluoroprostaglandin-F.sub.2                                     and                                                     deoxy-11β-hydroxymethyl-                                                                         8-iso-11-deoxy-11α-hydroxymethyl-16,16-di                                fluoro-                                                 16,16-difluoroprosta-  prostaglandin-F.sub.2α                            glandin-E.sub.2 and 8-iso-11-                                                  deoxy-11α-hydroxymethyl-                                                 16,16-difluoroprosta-                                                          glandin-E.sub.2 (Ex. 178)                                                  __________________________________________________________________________     Ex-                  Method                                                    ample                                                                              Starting prostaglandin E                                                                        of Example                                                                           Product Prostaglandin Fα                      __________________________________________________________________________     292 l-11-deoxy-11α-(1-hydroxy-                                                                80    l-11-deoxy-11α-(1-hydroxyethyl)-13-dihydr                                o-                                                      ethyl)-13-dihydroprosta-                                                                              prostaglandin-F.sub.1α  and                                              11-deoxy-11α-(1-hydroxy-                          glandin-E.sub.1  and 11-deoxy-11α-                                                              ethyl)-13-dihydroprostaglandin-F.sub.1α                                  and 8-iso-                                              (1-hydroxyethyl)-13-di-                                                                               11-deoxy-11α-(1-hydroxyethyl)-13-dihydro-                                M                                                       hydroprostaglandin-E.sub.1  and                                                                       prostaglandin-F.sub.1                                   8-iso-11-deoxy-11α-(1-                                                   hydroxyethyl)-13-dihydro-                                                      prostaglandin-E.sub.1  (Ex. 169)                                           293 l-11-deoxy-11α-(1-hydroxy-1-                                                              80    l-11-deoxy-11α-(1-hydroxy-1-methylethyl)-                                a                                                       methylethyl)prostaglandin-                                                                            prostaglandin-F.sub.1α                            E.sub.1 (Ex. 170)                                                          294 l-11-deoxy-11α-hydroxy-                                                                   80    l-11-deoxy-11α-hydroxymethyl-prostaglandi                                n-F.sub.3α                                        methyl-prostaglandin-E.sub.3                                                                          and l-11-deoxy-11α-hydroxymethylprostagla                                ndin-                                                   and l-11-deoxy-11α-hydroxy-                                                                     F.sub.3α  and 8-iso-11-deoxy-11α-hy                                droxymethylprosta-                                      methylprostaglandin-E.sub.2 and                                                                       glandin-F.sub.3α                                  8-iso-11-deoxy-11α-hydroxy-                                              methylprostaglandin-E.sub.3                                                    (Ex. 171)                                                                  295 l-11-deoxy-11α-hydroxy-                                                                   80    l-11-deoxy-11α-hydroxymethyl-15-epiprosta                                -                                                       methyl-15-epiprostaglandin-                                                                           glandin-F.sub.2α and l-11-deoxy-11α                                -hydroxymethyl-                                         E.sub.2 and l-11-deoxy-11α-hy-                                                                  15-epiprostaglandin-F.sub.2α  and                                        8-iso-11-deoxy-11α-                               droxymethyl-15-epiprosta-                                                                             hydroxymethyl-15-epiprostaglandin-F.sub.2.alpha                                .                                                       glandin-E.sub.2 and 8-iso-11-                                                  deoxy-11α-hydroxymethyl-15-                                              epiprostaglandin-E.sub.2 (Ex. 172)                                         296 l-11-deoxy-11α-(1-hydroxy-1-                                                              81    l-11-deoxy-11α-(1-hydroxy-1-methylethylac                                etyl-                                                   methylethylacetylprosta-                                                                              prostaglandin-F.sub.2α methyl ester               glandin-E.sub.2 methyl ester                                                   (Ex. 173)                                                                  297 l-11-deoxy-11α-hydroxy-                                                                   80    l-11-deoxy-11α-hydroxymethyl-20-ethylpros                                ta-                                                     methyl-20-ethylprostaglandin-                                                                         glandin-F.sub.2 ; l-11-deoxy-11β-hydroxyme                                thyl-20-                                                E.sub.2 ; l-11-deoxy-11β-hydroxy-                                                                ethylprostaglandin-F.sub.2α and                                          8-iso-11-deoxy-                                         methyl-20-ethylprostaglandin-                                                                         11α-hydroxymethyl-20-ethylprostaglandin-F                                .sub.2α                                           E.sub.2 and 8-iso-11-deoxy-11α-                                          hydroxymethyl-20-ethyl-                                                        prostaglandin-E.sub.2 (Ex. 179)                                            298 dl-11-deoxy-11α-hydroxy-                                                                  80    dl-11-deoxy-11α-hydroxymethyl-17,20-tetra                                nor-                                                    methyl-17,20-tetranor-16-m-                                                                           16-m-trifluoromethylphenoxyprostaglandin-               trifluoromethylphenoxy-                                                                               F.sub.2α ; dl-11-deoxy-11β-hydroxyme                                thyl-17,20-                                             prostaglandin-E.sub.2 ; dl-11-                                                                        tetranor-16-m-trifluoromethylphenoxyprosta-             deoxy-11β-hydroxymethyl-                                                                         glandin-F.sub.2α and dl-8-iso-11-deoxy-11                                α-hydroxy-                                        17,20-tetranor-16-m-tri-                                                                              methyl-17,20-tetanor-16-m-trifluoromethyl-              fluoromethylphenoxyprosta-                                                                            prostaglandin-F.sub.2α                            glandin-E.sub.2 and dl-8-iso-                                                  11-deoxy-11α-hydroxymethyl-                                              17,20-tetranor-16-m-tri-                                                       fluoromethylprostaglandin-                                                     E.sub.2 (Ex. 180)                                                          299 l-11-deoxy-11α-(-hydroxy-1-                                                               80    l-11-deoxy-11α-(1-hydroxy-1-methylethyl)-                                0                                                       methylethyl)-17,20-tetranor-                                                                          17,20-tetranor-16-p-fluorophenoxyprosta-                16-p-fluorophenoxyprosta-                                                                             glandin-F.sub.2                                         glandin-E.sub.2 (Ex. 181)                                                  300 l-11-deoxy-11α-hydroxymethyl-                                                             80    l-11-deoxy-11α-hydroxymethyl-17,20-tetran                                or-                                                     17,20-tetranor-16-m-chloro-                                                                           16-m-chlorophenoxyprostaglandin-F.sub.2α                                 ; l-11-                                                 phenoxyprostaglandin-E.sub.2 ; l-                                                                     11β-hydroxymethyl-17,20-tetranor-16-m-             11-deoxy-11β-hydroxymethyl-                                                                      chlorophenoxyprostaglandin-F.sub.2α and                                  l-8-iso-                                                17,20-tetranor-16-m-chloro-                                                                           11-deoxy-11α-hydroxymethyl-17,20-tetranor                                -                                                       chlorophenoxyprostaglandin-                                                                           16-m-chlorophenoxyprostaglandin-F.sub.2α                                 n                                                       E.sub.2 and l-8-iso-11-deoxy-11α-                                        hydroxymethyl-17,20-tetranor-                                                  16-m-chlorophenoxyprosta-                                                      glandin-E.sub.2                                                            301 l-11-deoxy-11α-(1,3-dioxoan-                                                              80    l-11-deoxy-11α-(1,3)-dioxolan-2-yl)-13-di                                hydro-                                                  2-yl)-1,3-dihydroprosta-                                                                              prostaglandin-F.sub.1α                            glandin-E.sub.1 (Ex. 186)                                                  302 l-11-deoxy-11α-(2-methyl-                                                                 80    l-11-deoxy-11α-(2-methyl-1,3-dioxolan-2-y                                l)-                                                     1,3-dioxolan-2-yl)prosta-                                                                             prostaglandin-F.sub.1α                            glandin-E.sub.1 (Ex. 187)                                                  303 l-11-deoxy-11α-(1,3-dioxolan-                                                             80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-prosta                                -                                                       2-yl)-prostaglandin-E.sub.3                                                                           glandin-F.sub.3α                              304 l-11-deoxy-11α-(1,3-dioxolan-                                                             80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-epi                                -                                                       2-yl)-15-epi-prostaglandin-                                                                           prostaglandin-F.sub.2α                            E.sub.2 (Ex. 189)                                                          305 dl-11-deoxy-11α-(1,3-dioxolan-                                                            80    dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-prost                                a-                                                      2-yl)-prostaglandin-E.sub.2                                                                           glandin-F.sub.2α                                  (Ex. 190)                                                                  306 l-11-deoxy-11α-(1,3-dioxolan-                                                             81    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-15-met                                hyl-                                                    2-yl)-15-methylprostaglandin-                                                                         prostaglandin-F.sub.  1α methyl ester             E.sub.1 methyl ester (Ex. 191)                                             307 l-11-deoxy-11α-(2-methyl-                                                                 80    l-11-deoxy-11α-(2-methyl-1,3-dioxolan-2-y                                l)-                                                     1,3-dioxolan-2-yl)-16,16-                                                                             16,16-dimethylprostaglandin-F.sub.2α              dimethylprostaglandin-E.sub.2                                              308 l-11-deoxy-11α-(1,3-dioxolan-                                                             80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-16(R)m                                ethyl-                                                  2-yl)-16(R)-methylprosta-                                                                             prostaglandin-F.sub.2α                            glandin-E.sub.2 (Ex. 193)                                                  309 l-11-deoxy-11α-(1,3-dioxolan-                                                             80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-16,16-                                di-                                                     2-yl)-16,16-difluoroprosta-                                                                           fluoroprostaglandin-F.sub.2α                      glandin-E.sub.2 (Ex. 194)                                                  310 l-11-deoxy-11α-(1,3-dioxolan-                                                             80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-20-eth                                yl-                                                     2-yl)-20-ethylprostaglandin-                                                                          prostaglandin-F.sub.2α                            E.sub.2 (Ex. 195)                                                          311 dl-11-deoxy-11α-(1,3-                                                                     80    dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,20                                -                                                       dioxolan-2-yl)-17,20-  tetranor-16-m-trifluoromethylphenoxyprosta-             tetranor-16-m-trifluoro-                                                                              glandin-F.sub.2α                                  methylphenoxyprostaglandin-                                                    E.sub.2 (Ex. 196)                                                          312 l-11-deoxy-11α-(1,3-dioxo-                                                                80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,20-                                N                                                       lan-2-yl)-17,20-tetranor-                                                                             tetranor-16-p-fluorophenoxyprostaglandin-F.sub.                                2α                                                16-p-fluorophenoxyprosta-                                                      glandin-E.sub.2 (Ex. 197)                                                  313 l-11-deoxy-11α-(1,3-dioxo-                                                                80    l-11-deoxy-11α-(1,3-dioxolan-2-yl)-17,20-                                8                                                       lan-2-yl)-17,20-tetranor-                                                                             tetranor-16-m-chlorophenoxyprostaglandin-F.sub.                                2α                                                16-m-chlorophenoxyprosta-                                                      glandin-E.sub.2 (Ex. 198)                                                  __________________________________________________________________________     Ex- Starting 11-deoxy-11α/β-                                                             Method                                                                               Product 11-deoxy-11α/β-mercaptoprost                                a-                                                  ample                                                                              alkanoylthioprostaglandin E                                                                     of Example                                                                           glandin E                                           __________________________________________________________________________     314 l-11-deoxy-11α-propanoylthio-                                                             80    l-11-deoxy-11α-mercapto-13-dihydroprostag                                landin-                                                 13-dihydroprostaglandin-F.sub.1                                                                       F.sub.1α and 11-deoxy-11β-propanoylt                                hiol-13-di-                                             and 11-deoxy-11β-propanoylthio-                                                                  dihydroprostaglandin-F.sub.1α                     13-dihydroprostaglandin-E.sub.  1                                              (Ex. 223)                                                                  315 l-11-deoxy-11α-acetylthioprosta-                                                          80    l-11-deoxy-11α-mercaptoprostaglandin-F.su                                b.2α and                                          glandin-E.sub.3 and l-11-deoxy-11β-                                                              l-11-deoxy-11β-mercaptoprostaglandin-F.sub                                .3α                                               acetylthioprostaglandin-E.sub.3                                                (Ex. 224)                                                                  316 l-11-deoxy-11α-acetylthio-                                                                80    l-11-deoxy-11α-mercaptoprostaglandin-F.su                                b.2α                                              prostaglandin-E.sub.2 methyl ester                                                                    methyl ester and l-11-deoxy-11β-mercaptopr                                osta-                                                   and l-11-deoxy-11β-acetylthio-                                                                   glandin-F.sub.2α methyl ester                     prostaglandin-E.sub.2 methyl ester                                             (Ex. 225)                                                                  317 l-11-deoxy-11α-acetylthio-                                                                80    l-11-deoxy-11α-mercaptoprostaglandin-15-e                                pi-                                                     15-epi-prostaglandin-E.sub.2 and                                                                      prostaglandin-F.sub.2α and                                               l-11-deoxy-11β-mercapto-                           l-11-deoxy-11β-acetylthio-                                                                       15-epiprostaglandin-F.sub.2α                      15-epiprostaglandin-E.sub.2                                                    (Ex. 226)                                                                  318 dl-11-deoxy-11α-acetylthio-                                                               80    dl-11-deoxy-11α-mercaptoprostaglandin-E.s                                ub.1α and                                         prostaglandin-E.sub.1 and dl-11-                                                                      dl-11-deoxy-11β-mercaptoprostaglandin-F.su                                b.1α                                              deoxy-11β-acetylthiol-                                                    prostaglandin-E.sub.1 (Ex. 227)                                            319 l-11-deoxy-11α-acetylthio-                                                                80    l-11-deoxy-11α-mercapto-16,16-dimethylpro                                sta-                                                    16,16-dimethylprostaglandin-                                                                          glandin-F.sub.1α and l-11-deoxy-11β-                                mercapto-16,16-                                         E.sub.1 and l-11-deoxy-11β-acetyl-                                                               dimethylprostaglandin-F.sub.1α                    thio-16,16-dimethylprosta-                                                     glandin-E.sub.1 (Ex. 228)                                                  320 l-11-deoxy-11α-acetylthiol-                                                               80    l-11-deoxy-11α-mercapto-16,16-dimethylpro                                sta-                                                    16,16-dimethylprostaglandin-                                                                          glandin-F.sub.2α and l-11-deoxy-11β-                                mercapto-16,16-                                         E.sub.2 and l-11-deoxy-11β-                                                                      dimethylprostaglandin-F.sub.2α                    acetylthio-16,16-dimethyl-                                                     prostaglandin-E.sub.2 (Ex. 229)                                            321 l-11-deoxy-11α-acetylthiol-                                                               80    l-11-deoxy-11α-mercapto-16,16(S)-methylpr                                osta-                                                   16(S)methylprostaglandin-E.sub.2                                                                      glandin-F.sub.2α and l-11-deoxy-11β-                                mercapto-16(S)-                                         and l-11-deoxy-11β-acetyl-                                                                       methylprostaglandin-F.sub.2α                      thio-16(S)-methylprosta-                                                       glandin-E.sub.2 (Ex. 230)                                                  322 l-11-deoxy-11α-acetylthio-                                                                80    l-11-deoxy-11α-mercapto-16-fluoroprostagl                                andin-                                                  16-fluoroprostaglandin-E.sub.2                                                                        F.sub.2α and l-11-deoxy-11β-mercapto                                -16-fluoro-                                             and l-11-deoxy-11β-acetyl-                                                                       prostaglandin-F.sub.2α                            thio-16-fluoroprostaglandin-                                                   E.sub.2 (Ex. 231)                                                          323 l-11-deoxy-11α-acetylthio-20-                                                             80    l-11-deoxy-11α-mercapto-20-methylprostagl                                andin-                                                  methylprostaglandin-E.sub.2 and                                                                       E.sub.2α and l-11-deoxy-11β-mercapto                                -20-methyl-                                             l-11-deoxy-11β-acetylthiol-20-                                                                   prostaglandin-F.sub.2α                            methylprostaglandin-E.sub.2 (Ex. 232)                                      324 dl-11-deoxy-11α-acetylthio-                                                               80    dl-11-deoxy-11α-mercapto-17,20-tetranor-1                                6-m-                                                    17,20-tetranor-16-m-trifluoro-                                                                        trifluoromethylphenoxyprostaglandin-E.sub.2                                    and                                                     methylphenoxyprostaglandin-E.sub.2                                                                    dl-11-deoxy-11β-mercapto-17,20-tetranor-16                                -m-                                                     and dl-11-deoxy-11β-acetyl-                                                                      trifluoromethylphenoxyprostaglandin-E.sub.2             thiol-17,20-tetranor-16-m-tri-                                                 fluoromethylphenoxyprosta-                                                     glandin-E.sub.2 (Ex. 233)                                                  325 l-11-deoxy-11α-acetylthio-                                                                80    l-11-deoxy-11α-mercapto-17,20-tetranor-16                                -p-                                                     17,20-tetranor-16-p-fluoro-                                                                           fluorophenoxyprostaglandin-F.sub.2α and                                  l-11-deoxy-                                             phenoxyprostaglandin-E.sub.2 and                                                                      11β-mercapto-17,20-tetranor-16-p-fluorophe                                n-                                                      l-11-deoxy-11β-acetylthiol-                                                                      oxyprostaglandin-F.sub.2α                         17,20-tetranor-16-p-fluoro-                                                    phenoxyprostaglandin-E.sub.2                                                   (Ex. 234)                                                                  326 l-11-deoxy-11α-acetylthio-                                                                80    l-11-deoxy-11α-mercapto-17,20-tetranor-16                                -m-                                                     17,20-tetranor-16-m-chloro-                                                                           chlorophenoxyprostaglandin-F.sub.2α  and                                 l-11-deoxy-                                             phenoxyprostaglandin-E.sub.2                                                                          11β-mercapto-17,20-tetranor-16-m-chloro-           and l-11-deoxy-11β-acetyl-                                                                       phenoxyprostaglandin-F.sub.2α                     thio-17,20-tetranor-16-m-                                                      chlorophenoxyprostaglandin-                                                    E.sub.2 (Ex. 235)                                                          __________________________________________________________________________

EXAMPLES 327-343

Hydrolysis of the starting prostaglandins of the table below by the method of Example 217 is productive of the product prostaglandins of the table.

    __________________________________________________________________________     Ex-                                                                            ample                                                                              Starting Prostaglandin                                                                            Product                                                 __________________________________________________________________________     327 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-13-                                                      l-11-deoxy-11α-(formyl)-13-dihydroprosta-             dihydroprostaglandin-F.sub.1α (Ex. 301)                                                     glandin-E.sub.1α                                  328 l-11-deoxy-11α-(2-methyl-1,3-dioxolan-                                                      l-11-deoxy-11α-(acetyl)-prostaglandin-F.sub.1                            α                                                     2-yl)-prostaglandin-F.sub.1α (Ex. 302)                               329 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                         l-11-deoxy-11α-(formyl)-prostaglandin-F.sub.3                            α                                                     prostaglandin-F.sub.3α (Ex. 303)                                     330 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                         l-11-deoxy-11α-(formyl)-15-epi-prostaglandin-                            1                                                           15-epi-prostaglandin-F.sub.2α (Ex. 304)                                                     F.sub.2α                                          331 dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        dl-11-deoxy-11α-(formyl)-prostaglandin-F.sub.                            2α                                                    prostaglandin-F.sub.2α (Ex. 305)                                     332 l-11-deoxy-11α(1,3-dioxolan-2-yl)-                                                          l-11-deoxy-11α-(formyl)-15-methylprostaglandi                            n-                                                          15-methylprostaglandin-F.sub.1α methyl                                                      F.sub.1α methyl ester                                 ester (Ex. 306)                                                            333 l-11-deoxy-11α-(2-methyl-1,3-dioxolan-                                                      l-11-deoxy-11α-(acetyl)-16,16-dimethylprosta-                            2                                                           2-yl)-16,16-dimethylprostaglandin-                                                                glandin-F.sub.2α                                      F.sub.2α (Ex. 307)                                                   334 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                         l-11-deoxy-11α-(formyl)-16(R)-methylprosta-           16(R)-methylprostaglandin-F.sub.2α                                                          glandin-F.sub.2α                                      (Ex. 308)                                                                  335 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                         l-11-deoxy-11α-(formyl)-16,16-difluoroprosta-                            `                                                           16,16-difluoroprostaglandin-F.sub.2α                                                        glandin-F.sub.2α                                      (Ex. 309)                                                                  336 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                         l-11-deoxy-11α-(formyl)-20-ethylprostaglandin                            -                                                           20-ethylprostaglandin-F.sub.2α                                                              F.sub.2α                                              (Ex. 310)                                                                  337 dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        dl-11-deoxy-11α-(formyl)-17,20-tetranor-16-m-                            3                                                           17,20-tetranor-16-m-trifluoromethyl-                                                              trifluoromethylphenoxyprostaglandin-F.sub.2α                             '                                                           phenoxyprostaglandin-F.sub.2α (Ex. 311)                              338 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                         l-11-deoxy-11α-(formyl)-17,20-tetranor-16-p-                             Z                                                           17,20-tetranor-16-p-fluorophenoxy-                                                                fluorophenoxyprostaglandin-F.sub.2α                   prostaglandin-F.sub.2α (Ex. 312)                                     339 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                         l-11-deoxy-11α-(formyl)-17,20-tetranor-16-m-                             4                                                           17,20-tetranor-16-m-chlorophenoxy-                                                                chlorophenoxyprostaglandin-F.sub.2α                   prostaglandin-F.sub.2α (Ex. 313)                                     340 l-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                         l-11-deoxy-11α-(formyl)-prostaglandin-F.sub.2                            α                                                     prostaglandin-F.sub.2α (Ex. 215)                                     341 dl-11-deoxy-11α-(1,3-dioxolan-2-yl)-                                                        dl-11-deoxy-11α-(formyl)-17,20-tetranor-16-p-                            v                                                           17,20-tetranor-16-p-fluoroprosta-                                                                 fluoroprostaglandin-F.sub.2α                          glandin-F.sub.2α (Ex. 216)                                           __________________________________________________________________________     Ex-                                                                            ample                                                                              Starting E Prostaglandins                                                                         Product F Prostaglandins                                __________________________________________________________________________     342 l-11-deoxy-11β-(1,3-dioxolan-2-yl)-                                                          l-11-deoxy-11β-(formyl)-prostaglandin-F.sub.2.                            alpha.                                                      prostaglandin-F.sub.2α and F.sub.2β (Ex.                                               and F.sub.2β                                       343 l-11-deoxy-11β-(1,3-dioxolano-2-yl)-                                                         l-11-deoxy-11α-(formyl)-17,20-tetranor-p-             17,20-tetranor-16-p-fluoroprosta-                                                                 fluoroprostaglandins-F.sub.2α and                                        F.sub.2β                                               glandins-F.sub.2α and F.sub.2β (Ex. 211)                        __________________________________________________________________________ 

We claim:
 1. A compound selected from the group consisting of an optically active compound of the formula: ##STR11## and the racemic mixture of that compound and its mirror image, wherein R₁ is a lower alkyl group; R₂ is selected from the group consisting of hydroxy, lower alkanoyloxy, lower alkylsulfonyloxy, tetrahydropyranyloxy, and tri-(lower alkyl)silyloxy; R₃ is selected from the group consisting of hydrogen and an alkyl group having from 1 to 12 carbon atoms; and the pharmaceutically acceptable cationic salts thereof when R₃ is hydrogen.
 2. A compound in accordance with claim 1 selected from the group consisting of the formula: ##STR12## wherein R₁ is selected from the group consisting of methyl and ethyl, R₃ is selected from the group consisting of hydrogen and methyl, and the non-toxic cationic salts thereof when R₂ is hydrogen.
 3. The optically active compound according to claim 2 wherein R₁ is methyl, and R₃ is methyl; 11-deoxy-11α-methylprostaglandin E₁ methyl ester.
 4. The optically active compound according to claim 2 wherein R₁ is ethyl, and R₃ is methyl; 11-deoxy-11α-ethylprostaglandin E₁ methyl ester.
 5. The optically active according to claim 2 wherein R₁ is ethyl,; 11-deoxy-11α-ethylprostaglandin E₁.
 6. The optically active compound according to claim 2 wherein R₁ is α-methyl; 11α-methyl-11-deoxyprostaglandin E₁. 